Anticancer indenes, indanes, azaindenes, azaindanes, pharmaceutical compositions and uses

ABSTRACT

Disclosed are compounds for medical uses, for example, compounds of formula (Ia), wherein A1, A2, A3, A4, A5, A6, A7, R6, R7 and E are as described herein, pharmaceutical compositions containing such compounds, and methods of treating or preventing a disease or condition, for example, cancer.

CROSS-REFERENCE TO A RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 62/662,999, filed Apr. 26, 2018, the disclosure of whichis incorporated herein in its entirety for all purposes.

BACKGROUND OF THE INVENTION

Cancer is a leading cause of death in the developed world, with over onemillion people diagnosed and more than 500,000 deaths per year in theUnited States alone. Overall it is estimated that at least one in threepeople will develop some form of cancer during their lifetime. There aremore than 200 different histopathological types of cancer, four of which(breast, lung, colorectal, and prostate) account for over half of allnew cases in the U.S. (Jemal et al., Cancer J. Cin., 53, 5-26 (2003)).

Many of these tumors arise from mutations that activate Ras proteins,which control critically important cellular signaling pathways thatregulate growth and other processes associated with tumorigenesis. Thename “Ras” is an abbreviation of “Rat sarcoma” reflecting the way thefirst members of the Ras protein family were discovered. The name “ras”also is used to refer to the family of genes encoding these proteins.

Ras-driven cancers have remained the most intractable diseases to anyavailable treatment. New therapeutic and preventative strategies areurgently needed for such cancers (Stephen et al., Cancer Cell, 25:272-281 (2014)). Drug discovery programs worldwide have soughtRas-selective drugs for many years, but heretofore no avail (Spiegel etal., Nature Chem. Biol., 10: 613-622 (2014)). New drugs that selectivelytarget abnormal or mutant Ras and/or Ras-mediated pathological processesin patients' tumors will enable highly efficacious treatments of suchpatients while minimizing toxicity to cells and tissues with normal Rasfunctions (Stephen et al., supra; Spiegel et al., supra).

Ras proteins are key regulators of several aspects of normal cell growthand malignant transformation, including cellular proliferation, survivaland invasiveness, tumor angiogenesis and metastasis (Downward, NatureRev. Cancer, 3: 11-22 (2003)). Ras proteins are abnormally active inmost human tumors due to mutations in the ras genes themselves, or inupstream or downstream Ras pathway components, or other alterations inRas signaling. Targeted therapies that inhibit Ras-mediated pathwaystherefore are expected to inhibit the growth, proliferation, survivaland spread of tumor cells having activated or mutant Ras. Some such newexperimental therapeutic agents have shown promising activity inpreclinical studies, albeit with only modest activity in human clinicaltrials.

Genetic mutations in ras genes were first identified in human cancerover 3 decades ago. Such mutations result in the activation of one ormore of three major Ras protein isoforms, including H-Ras, N-Ras, orK-Ras, that turn on signaling pathways leading to uncontrolled cellgrowth and tumor development. Activating ras gene mutations occur denovo in approximately one third of all human cancers and are especiallyprevalent in pancreatic, colorectal, and lung tumors. Ras mutations alsodevelop in tumors that become resistant to chemotherapy and/orradiation, as well as to targeted therapies, such as receptor tyrosinekinase inhibitors (Gysin et al., Genes Cancer, 2: 359-372 (2011)). Whileras mutations are relatively infrequent in other tumor types, forexample, breast cancer, Ras can be pathologically activated by certaingrowth factor receptors that signal through Ras.

Although ras gene mutations have been known for many years, therecurrently are no available cancer therapeutics approved by the U.S. Foodand Drug Administration that are known to selectively suppress thegrowth of tumors driven by activated Ras. In fact, Ras has beendescribed as “undruggable” because of the relative abundance in cellsand high affinity for its substrate, GTP (Takashima and Faller, ExpertOpin. Ther. Targets, 17: 507-531 (2013)).

In addition to its role in cancer, activated Ras is important in avariety of other diseases, collectively referred to as “rasopathies.”One such disease, neurofibromatosis type 1 (NF1), a very prevalentautosomal dominant heritable disease, is caused by a mutation inneurofibromin, a Ras GAP (inactivating protein), which results in Rashyperactivation in the relatively common event of loss of the second NF1allele. Such mutations reportedly affect 1:3000 live births. The worstsymptoms associated with NF1 include numerous benign tumors(neurofibromas) arising from precursor nerve cells and Schwann cells ofthe peripheral nervous system. These tumors can cause severe problemsdepending on their location within the body, such as hearing or visionloss, as well as disfiguring masses on visible areas. Less common butextremely serious complications may arise when central nervous systemgliomas develop or plexiform neurofibromas become transformed, resultingin the development of metastatic peripheral nerve sheath tumors (Tidymanand Rauen, Curr. Opin. Genet. Dev., 19: 230-236 (2009)). Another raredevelopmental disease which is attributable to hyperactive H-Ras isCostello syndrome. This condition causes a range of developmentalabnormalities as well as predisposing patients to a variety of benignand malignant neoplasms (Tidyman and Rauen, supra).

Several approaches to treat diseases that arise from activating rasmutations have been undertaken. Because full maturation of the Rasprotein requires lipid modification, attempts have been made to targetthis enzymatic process with inhibitors of farnesyl transferase andgeranylgeranyltransferase, but with limited success and significanttoxicity. Targeting of downstream components of Ras signaling withinhibitors of Raf/Mek/Erk kinase components of the cascading pathway hasbeen an extremely active area of pharmaceutical research, but alsofraught with difficulties and paradoxes arising from complex feedbacksystems within the pathways (Takashima and Faller, supra).

Inhibitors targeting components within the PI3K/Akt pathway also havenot been successful as single agents, but presumably might synergizewith Raf/Mek/Erk pathway inhibitors to block Ras-dependent tumor growthand survival. Similarly, several other molecular targets have beenidentified from RNAi screening, which might provide new opportunities toinhibit the growth of Ras-driven tumors; such other potential targetsinclude CDK4, Cyclin D1, Tiam1, Myc, STK33, and TBK, as well as severalgenes involved in mitosis (Takashima and Faller, supra).

The nonsteroidal anti-inflammatory drug, sulindac (FIG. 1) has beenreported to selectively inhibit proliferation of cultured tumor cellshaving ras mutations (Herrmann et al., Oncogene, 17: 1769-1776 (1998)).Extensive chemical modifications of sulindac and the related NSAID,indomethacin, have been aimed at removing cyclooxygenase-inhibitoryactivity, while improving anticancer activity (Gurpinar et al., Mol.Cancer Ther., 12: 663-674 (2013); Romeiro et al., Eur. J. Med. Chem.,44: 1959-1971 (2009); Chennamaneni et al., Eur. J. Med. Chem., 56: 17-29(2012)). An example of a highly potent antiproliferative derivative is ahydroxy-substituted indene derivative of sulindac, OSIP-487703 (FIG. 1),that was reported to arrest colon cancer cells in mitosis by causingmicrotubule depolymerization (Xiao et al., Mol. Cancer Ther., 5: 60-67(2006)). OSIP-487703 also was reported to inhibit the growth and induceapoptosis of human SW480 colon cancer cells. These properties of mitoticarrest and microtubule disruption were shared by several additionalrelated compounds, including a pyridine (CP461) and trimethoxy (CP248)substituted variants (FIG. 1) (Lim et al., Clin. Cancer Res, 9:4972-4982 (2003); Yoon et al., Mol. Cancer Ther., 1: 393-404 (2002)).However, there was no reported association of antitumor properties ofthese compounds (FIG. 1) with Ras function, but rather such propertieswere attributed to direct binding to the microtubule subunit, tubulin,thereby causing mitotic arrest and blocking cell division. Still otherreports describe their ability to induce apoptosis by inhibition of cGMPphosphodiesterase (Thompson et al., Cancer Research, 60: 3338-3342(2000)).

Other investigators reported that sulindac sulfide (FIG. 1) can inhibitRas-induced malignant transformation, possibly by decreasing the effectsof activated Ras on its main effector, the c-Raf-1 kinase, due to directbinding to the ras gene product p21 in a non-covalent manner (Herrmannet al., supra). Sulindac sulfide also can inhibit focus formation, amarker of malignant transformation, by rat or mouse fibroblasts byforced Ras expression, but not by other transformation pathways (Gala etal., Cancer Lett., 175: 89-94 (2002); Herrmann et al., supra). Sulindacsulfide was reported also to bind Ras directly and interfere withnucleotide exchange. Several groups additionally reported that sulindacinterferes with Ras binding to the downstream signaling kinase c-Raf,and blocks activation of downstream signaling or transcription (Herrmannet al., supra; Pan et al., Cell Signal., 20: 1134-1141 (2008)).

The previous findings led to efforts to improve the Ras inhibitoryactivity of sulindac sulfide through chemical modifications (Karaguni etal., Bioorg. Med. Chem. Lett., 12: 709-713 (2002)). Several derivativeswere identified that were more potent inhibitors of tumor cellproliferation, and four related compounds (FIG. 2) exhibited selectivitytowards a Ras-transfected MDCK cell line compared to the parental cellline. Three of these compounds also potently disrupted the Ras-Rafinteraction. However, none of the four were more potent toward themutant K-Ras-bearing SW-480 cell line, although they did inhibit Erkphosphorylation and bound weakly to the G-domain of H-Ras (Waldmann etal., Angew. Chem. Int. Ed. Engl., 43: 454-458 (2004)).

In addition to sulindac sulfide, the non-COX inhibitory sulfonemetabolite of sulindac has been reported to have selective effects ontumor cells with mutant Ras. For example, transfection of Caco-2 colontumor cells with the activated K-Ras oncogene caused cells treated witheither sulindac sulfide or sulfone to undergo apoptosis earlier thannon-transfected cells. (Lawson et al., Cancer Epidemiol. BiomarkersPrev., 9: 1155-62 (2000)). Other investigators have reported thatsulindac sulfone can inhibit mammary tumorigenesis in rats and that theeffect was greater on tumors with the mutant H-Ras genotype (Thompson etal., Cancer Research 57: 267-271 (1997)). However, other investigatorsreport that the inhibition of colon tumorigenesis in rats by eithersulindac or sulindac sulfone occurs independently of K-Ras mutations (deJong et al., Amer. J. Physio. Gastro and Liver Phys. 278: 266-272(2000)). Yet other investigators report that the K-Ras oncogeneincreases resistance to sulindac-induced apoptosis in rat enterocytes(Arber et al., Gastroenterology, 113: 1892-1900 (1997)). As such, theinfluence of Ras mutations on the anticancer activity of sulindac andits metabolites is controversial and unresolved, and not exploited toimprove anticancer potency or selectivity.

Certain other compounds have been described with selective toxicitytoward cells expressing activated Ras. A high-throughput phenotypicscreen of over 300,000 compounds was conducted within NIH MolecularLibraries Screening Center program to identify compounds which weresynthetically lethal to cells expressing oncogenic H-Ras. A leadcompound, ML210, inhibited growth of cells expressing mutant Ras with anIC50 of 71 nM, and was 4-fold selective versus cells lacking oncogenicRas. Though the specific molecular target of ML210 (FIG. 3) is unknown,the compound was chemically optimized to eliminate reactive groups andimprove pharmacologic properties (ML210, Dec. 12, 2011 update, ProbeReports from NIH Molecular Libraries Program, Bethesda,http://www.ncbi.nlm.nih.gov/books/NBK98919/).

A separate high-throughput screen identified two compounds, RSL3 andRSL5 which induce non-apoptotic, Mek-dependent, oxidative cell death(Yang and Stockwell, Chem. Biol., 15: 234-245 (2008). RSL5, like apreviously identified Ras synthetic lethal compound, erastin, binds thevoltage-dependent anion channel (VDAC) (Dolma et al., Cancer Cell, 3:285-296 (2003)). Yet another small-molecule screen identified oncrasin,a compound selectively active against K-Ras mutant cell lines (Guo etal., Cancer Res., 68: 7403-7408 (2008)). One analog, NSC-743380 (FIG.3), is highly potent and has shown antitumor activity in a preclinicalmodel of K-Ras driven renal cancer (Guo et al., PLoS One, 6: e28487(2011)). A prodrug approach has recently been described for oncrasinderivatives, to improve stability, pharmacokinetics, and safety (Wu etal., Bioorg. Med. Chem., 22: 5234-5240 (2014)). A synthetic lethalscreen using embryonic fibroblasts derived from mice expressing theoncogenic K-Ras (G12D) identified a compound, lanperisone (FIG. 3), thatinduced non-apoptotic cell death via a mechanism involving oxidativestress (Shaw et al., Proc. Natl. Acad. Sci. USA, 108: 8773-8778 (2011)).In contrast to the synthetic lethal approach, a fragment-based screeningapproach paired with crystallographic studies has been used to identifycompounds which irreversibly bind to and inhibit K-Ras in lung tumorcells having the relatively rare G12C ras gene mutation (Ostrem et al.,Nature, 503: 548-551 (2013)). While compounds of this series potentlyinhibit Ras through a covalent interaction, the low frequency of thismutation may limit the utility of such compounds. Finally, a newinvestigational strategy for targeting oncogenic Ras has been described(Zimmerman et al., J. Med. Chem., 57: 5435-5448 (2014)) which involvesstructure guided design and kinetic analysis of benzimidazole inhibitorstargeting the PDES prenyl binding site.

WO 97/47303 and WO 2014/047592, U.S. Patent Application Publication Nos.2003/0009033 and 2003/0194750, U.S. Pat. Nos. 6,063,818; 6,071,934,5,965,619; 5,401,774; 6,538,029, 6,121,321, and UK Patent No. GB 1370028disclose certain anticancer compounds; however, these documents do notdisclose that the compounds have any Ras-specific activity, nor anybasis for a selective Ras-directed method of use.

We have disclosed (2015-2018) a series of compounds having an indene orindene-related core structure, such compounds having antitumorproperties, including Ras-inhibitory properties (U.S. Pat. Nos.9,862,698 and 9,931,315; U.S. Pat. App. Pub. Nos. US 2017/0342021 and US2018/0251443; PCT Intl. Pat. App. Nos. WO 2016/100542, WO 2016/100546;WO 2016/099452; WO 2017/106520). Chemical structures of all thesepreviously disclosed compounds are encompassed by the generic structureI shown in FIG. 4 wherein the substitutents for R, R₀, R₁-R₈, n, X, Y,Y′, and E are as described in the WO 2016/100542. Here we disclosenovel, indene-related compounds designed to further improve druglikeattributes, Ras-inhibitory antitumor properties and medical utility.

Cancer still is among the most prevalent causes of human deaths andsuffering worldwide, and there remains a vast unmet medical need for newcompounds that can be developed or made suitable for treating orpreventing cancers. There especially exists an unmet need for novelcompounds that inhibit Ras-dependent diseases or undesirable conditions.The present invention discloses new Ras-inhibitory antitumor compoundswith unique chemical structures, properties, medical utility andcommercial applicability distinct from any prior art.

BRIEF SUMMARY OF THE INVENTION

The invention provides a compound of formula Ia:

wherein:

A₁ is a nitrogen atom bonded to R₂₁ when R₂₁ is not bonded to A₂, or A₁is a nitrogen atom bonded to R₉ when R₂₁ is bonded to A₂; or, A₁ is acarbon atom bonded to R₉ and R₂₁ when R₂₁ is not bonded to A₂, or A₁ isa carbon atom bonded to R₈ and R₉ when R₂₁ is bonded to A₂;

A₂ is a nitrogen atom bonded to R₂₁ when R₂₁ is not bonded to A₁, or A₂is a nitrogen atom bonded to R₈ when R₂₁ is bonded to A₁; or, A₂ is acarbon atom bonded to R₈ and R₂₁ when R₂₁ is not bonded to A₁, or A₂ isa carbon atom bonded to R₈ and R₂ when R₂₁ is bonded to A₁;

A₃ is a nitrogen atom; or, or A₃ is a carbon atom bonded to R₅;

A₄ is a nitrogen atom; or, or A₄ is a carbon atom bonded to R₄;

A₅ is a nitrogen atom; or, or A₅ is a carbon atom bonded to R₃;

A₆ is a nitrogen atom; or, or A₆ is a carbon atom bonded to R₂;

A₇ is a nitrogen atom; or, or A₇ is a carbon atom bonded to R₁;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halo, alkyl, hydroxyl, haloalkyl, alkylmercapto, cyano and a substitutedor unsubstituted alkyloxy group;

R₂₁ is selected from —(CH₂)_(n)C(O)X and —(CH₂)_(n)NR₂₂C(O)X;

each of R₅, R₆, R₇, R₈, R₉, R₂₀, and R₂₂ is independently selected fromhydrogen, alkyl, halo and hydroxyl; or R₅ and R₆ together is acarbon-carbon bond when A₃ is a carbon atom; or R₅ and R₂₀ together is acarbon-carbon bond when A₂ and A₃ are carbon atoms; or R₉ and R₂₀together is a carbon-carbon bond when A₁ and A₂ are carbon atoms; or R₉and R₈ together is a carbon-nitrogen bond when A₁ is carbon and A₂ isnitrogen or when A₁ is nitrogen and A₂ is carbon; or R₅ and R₈ togetheris a carbon-nitrogen bond when A₂ is nitrogen and A₃ is carbon; or, R₆and R₇ together with the atom to which they are attached form a ring;or, when A₃ is carbon, R₅ and R₆ together with the atoms to which theyare attached form a ring;

n is 0, 1 or 2, or n is 1 or 2 when A₇ is a nitrogen atom;

X is selected from aryl, arylalkyl, heterocyclyl and heterocyclylalkyl,or X is NR′R″ where R′ is selected from aryl, arylalkyl, heterocyclyl,and heterocyclylalkyl, where the heterocyclyl of the heterocyclyl and ofthe heterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyland of the heterocyclylalkyl of the R′ when X is NR′R″, is selected from7-membered, 6-membered and 5-membered heterocyclic rings, and the arylof the aryl and arylalkyl, and the heterocyclyl of the heterocyclyl andof the heterocyclylalkyl, is optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxyl, alkyloxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy and sulfonamido;

R″ is selected from hydrogen, alkyl and haloalkyl;

E is a substituted or unsubstituted, saturated or unsaturated,9-membered, 8-membered, 7-membered, 6-membered, 5-membered, 4-memberedor 3-membered, carbocyclic or heterocyclic, monocyclic or bicyclic ring;or

(Z)- or (E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound;

with the proviso that when R₂₁ is —(CH₂)_(n)C(O)X, and each of A₂, A₄,A₅, A₆ and A₇ is a carbon atom, and R₉ and R₂₀ together is acarbon-carbon bond, and E is a substituted or unsubstituted, saturatedor unsaturated, 7-membered, 6-membered, 5-membered, 4-membered or3-membered carbocyclic or heterocyclic, monocyclic or bicyclic ring,then at least one of R₅, R₆ and R₇ is halo, or R₆ and R₇ together withthe atom to which they are attached form a ring, or R₅ and R₆ togetherwith the atoms to which they are attached form a ring, or at least oneof R₁, R₂, R₃, and R₄ or at least one substituent on the ring at E ishaloalkyloxy or is a substituted or unsubstituted group selected frompolyethyleneglycoxy, polyethyleneglycoxyalkyl, thioureido, borono,boronoalkyl, boronoalkyloxy, arylalkyloxy, aminosulfonyloxy,aminocarboxyl, aminocarbonylalkyloxy, aminocarbonylalkylthio,alkylcarbonylamino, aminoalkenylamino, alkylsulfonylamino, phosphono,phosphonothio, phosphonoamino, phosphonoalkyl, phosphonoalkylthio,phosphonoalkylamino, carboxyalkyl, carboxyalkenyl, carboxyalkynyl,carboxyalkyloxy, carboxyalkylamino, carboxyalkylthio, aminocarbonylthio,hydroxyalkyloxy, hydroxyalkylamino, hydroxyalkylthio, dialkylaminoalkyl,aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino,aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,alkyloxyaminocarbonyloxy, aminoalkylthio, alkylaminoalkylthio anddialkylaminoalkylthio, or any two substituents on E, together with theatoms to which they are attached, comprise an optionally substituted,saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic orheterocyclic ring that is not alkylenedioxy.

In a preferred embodiment, the invention provides a compound of formulaIa or a pharmaceutical composition thereof for use in treating a cancerpatient whose cancer has been assayed and found to contain a hyperactiveRas protein or a mutant ras gene encoding for a hyperactive Ras protein.

The invention also provides pharmaceutical compositions comprising atleast one novel compound of formula Ia for use in treating cancer,especially Ras-driven cancer, and methods of treating a cancer patient,particularly a cancer patient having a Ras-driven, with a compound offormula Ia or IIa.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

FIG. 1 depicts the chemical structures of sulindac and certainderivatives thereof reportedly having anticancer activity.

FIG. 2 depicts chemical structures of certain other sulindac derivativesreported to inhibit Ras.

FIG. 3 shows chemical structures of selective Ras-inhibitory compoundsidentified by synthetic lethal screening.

FIG. 4 depicts the generic structure I from WO 2016/100542 wherein thesubstituents for R, R₀, R₁-R₈, n, X, Y, Y′, and E are as described inthe WO 2016/100542.

FIG. 5 shows an example of Ras-selective tumor cell growth inhibitoryactivity of exemplary Ras inhibitory compound 2090; the data wereobtained according to the methods described in Examples 3 and 4; thesquare symbols are the HCT-116 data, the round symbols are the HT-29data.

FIG. 6 shows an example of Ras-selective tumor cell growth inhibitoryactivity of exemplary Ras inhibitory compound 2096; the data wereobtained according to the methods described in Examples 3 and 4; thesquare symbols are the HCT-116 data, the round symbols are the HT-29data.

FIG. 7 shows an example of Ras-selective tumor cell growth inhibitoryactivity of exemplary Ras inhibitory compound 2183; the data wereobtained according to the methods described in Examples 3 and 4; thesquare symbols are the HCT-116 data, the round symbols are the HT-29data.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a compound of formula Ia:

wherein:

A₁ is a nitrogen atom bonded to R₂₁ when R₂₁ is not bonded to A₂, or A₁is a nitrogen atom bonded to R₉ when R₂₁ is bonded to A₂; or, A₁ is acarbon atom bonded to R₉ and R₂₁ when R₂₁ is not bonded to A₂, or A₁ isa carbon atom bonded to R₈ and R₉ when R₂₁ is bonded to A₂;

A₂ is a nitrogen atom bonded to R₂₁ when R₂₁ is not bonded to A₁, or A₂is a nitrogen atom bonded to R₈ when R₂₁ is bonded to A₁; or, A₂ is acarbon atom bonded to R₈ and R₂₁ when R₂₁ is not bonded to A₁, or A₂ isa carbon atom bonded to R₈ and R₂₀ when R₂₁ is bonded to A₁;

A₃ is a nitrogen atom; or, or A₃ is a carbon atom bonded to R₅;

A₄ is a nitrogen atom; or, or A₄ is a carbon atom bonded to R₄;

A₅ is a nitrogen atom; or, or As is a carbon atom bonded to R₃;

A₆ is a nitrogen atom; or, or A₆ is a carbon atom bonded to R₂;

A₇ is a nitrogen atom; or, or A₇ is a carbon atom bonded to R₁;

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halo, alkyl, hydroxyl, haloalkyl, alkylmercapto, cyano and a substitutedor unsubstituted alkyloxy group;

R₂₁ is selected from —(CH₂)_(n)C(O)X and —(CH₂)_(n)NR₂₂C(O)X;

each of R₅, R₆, R₇, R₈, R₉, R₂₀, and R₂₂ is independently selected fromhydrogen, alkyl, halo and hydroxyl; or R₅ and R₆ together is acarbon-carbon bond when A₃ is a carbon atom; or R₅ and R₂₀ together is acarbon-carbon bond when A₂ and A₃ are carbon atoms; or R₉ and R₂₀together is a carbon-carbon bond when A₁ and A₂ are carbon atoms; or R₉and R₈ together is a carbon-nitrogen bond when A₁ is carbon and A₂ isnitrogen or when A₁ is nitrogen and A₂ is carbon; or R₅ and R₈ togetheris a carbon-nitrogen bond when A₂ is nitrogen and A₃ is carbon; or, R₆and R₇ together with the atom to which they are attached form a ring;or, when A₃ is carbon, R₅ and R₆ together with the atoms to which theyare attached form a ring;

n is 0, 1 or 2, or n is 1 or 2 when A₇ is a nitrogen atom;

X is selected from aryl, arylalkyl, heterocyclyl and heterocyclylalkyl,or X is NR′R″ where R′ is selected from aryl, arylalkyl, heterocyclyl,and heterocyclylalkyl, where the heterocyclyl of the heterocyclyl and ofthe heterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyland of the heterocyclylalkyl of the R′ when X is NR′R″, is selected from7-membered, 6-membered and 5-membered heterocyclic rings, and the arylof the aryl and arylalkyl, and the heterocyclyl of the heterocyclyl andof the heterocyclylalkyl, is optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxyl, alkyloxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, carboxamido, aldehydo, cyano,oxo, alkylcarbonyloxy and sulfonamido;

R″ is selected from hydrogen, alkyl and haloalkyl;

E is a substituted or unsubstituted, saturated or unsaturated,9-membered, 8-membered, 7-membered, 6-membered, 5-membered, 4-memberedor 3-membered, carbocyclic or heterocyclic, monocyclic or bicyclic ring;or

(Z)- or (E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound;

with the proviso that when R₂₁ is —(CH₂)_(n)C(O)X, and each of A₂, A₄,A₅, A₆ and A₇ is a carbon atom, and R₉ and R₂₀ together is acarbon-carbon bond, and E is a substituted or unsubstituted, saturatedor unsaturated, 7-membered, 6-membered, 5-membered, 4-membered or3-membered carbocyclic or heterocyclic, monocyclic or bicyclic ring,then at least one of R₅, R₆ and R₇ is halo, or R₆ and R₇ together withthe atom to which they are attached form a ring, or R₅ and R₆ togetherwith the atoms to which they are attached form a ring, or at least oneof R₁, R₂, R₃, and R₄ or at least one substituent on the ring at E ishaloalkyloxy or is a substituted or unsubstituted group selected frompolyethyleneglycoxy, polyethyleneglycoxyalkyl, thioureido, borono,boronoalkyl, boronoalkyloxy, arylalkyloxy, aminosulfonyloxy,aminocarboxyl, aminocarbonylalkyloxy, aminocarbonylalkylthio,alkylcarbonylamino, aminoalkenylamino, alkylsulfonylamino, phosphono,phosphonothio, phosphonoamino, phosphonoalkyl, phosphonoalkylthio,phosphonoalkylamino, carboxyalkyl, carboxyalkenyl, carboxyalkynyl,carboxyalkyloxy, carboxyalkylamino, carboxyalkylthio, aminocarbonylthio,hydroxyalkyloxy, hydroxyalkylamino, hydroxyalkylthio, dialkylaminoalkyl,aminoalkylamino, alkylaminoalkylamino, dialkylaminoalkylamino,aminoalkyloxy, alkylaminoalkyloxy, dialkylaminoalkyloxy,alkyloxyaminocarbonyloxy, aminoalkylthio, alkylaminoalkylthio anddialkylaminoalkylthio, or any two substituents on E, together with theatoms to which they are attached, comprise an optionally substituted,saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic orheterocyclic ring that is not alkylenedioxy.

In an embodiment, the compound is of formula Ia wherein A₇ is a carbonatom.

In another embodiment, the compound is of formula Ia wherein A₁ and A₃are carbon atoms.

In a further embodiment, the compound is of formula Ia wherein each ofA₁, A₂, A₃, A₄, A₅, A₆ and A₇ is a carbon atom.

In an additional embodiment, the compound is of formula Ia wherein R₂₁is —(CH₂)_(n)NR₂₂C(O)X.

In yet another embodiment, the compound is of formula Ia wherein R₂₁ is—(CH₂)_(n)C(O)X.

In a preferred embodiment of any one or more of the above embodimentseither individually or combined, the compound is of formula Ia where theheterocyclyl of the heterocyclyl and of the heterocyclylalkyl of X, orthe heterocyclyl of the heterocyclyl and of the heterocyclylalkyl of R′when X is NR′R″, is selected from azepanyl, oxazepanyl, thiazepanyl,azepinyl, oxepinyl, thiepanyl, homopiperazinyl, diazepinyl, thiazepinyl,piperidinyl, oxanyl, thianyl, pyridinyl, pyranyl, thiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,pyrimidinyl, pyrazinyl, pyridizinyl, oxazinyl, thiazinyl, dioxinyl,dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiaphenyl, pyrrolyl, furanyl, thiophenyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl.

In a preferred embodiment of the previous embodiment, the compound is offormula Ia wherein X is selected from heterocyclyl andheterocyclylalkyl, or X is NR′R″ where R′ is selected from heterocyclyl,and heterocyclylalkyl, where the heterocyclyl of the heterocyclyl and ofthe heterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyland of the heterocyclylalkyl of the R′ when X is NR′R″, is selected fromoxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl, dioxanyl,dithianyl, pyrimidinyl, pyrazinyl, pyridizinyl, oxazinyl, thiazinyl,dioxinyl, dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl,tetrahydrofuranyl, tetrahydrothiaphenyl, pyrrolyl, furanyl, thiophenyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl.

In a preferred embodiment of the previous embodiment, the compound is offormula Ia wherein the heterocyclyl of the heterocyclyl and of theheterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyl andof the heterocyclylalkyl of the R′ when X is NR′R″, is selected fromoxanyl, thianyl, pyranyl, thiopyranyl, thiomorpholinyl, dioxanyl,dithianyl, pyrimidinyl, pyrazinyl, pyridizinyl, oxazinyl, thiazinyl,dioxinyl, dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl,tetrahydrofuranyl, tetrahydrothiaphenyl, pyrrolyl, thiophenyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl.

In a preferred embodiment of the previous embodiment, the compound is offormula Ia wherein the heterocyclyl of the heterocyclyl and of theheterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyl andof the heterocyclylalkyl of the R′ when X is NR′R″, is selected fromdioxolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl andisothiazolyl.

In a preferred embodiment of any one or more of the above embodimentseither individually or combined, the compound is of formula Ia wherein Eis selected from aryl, pyridinyl, pyridizinyl, pyrimidinyl, pyrazinyl,benzopyrazolyl, benztriazolyl, indolyl, benzimidazolyl and indenyl, eachof which is substituted or unsubstituted.

In a preferred embodiment of the previous embodiment, E is phenyl andeach of A₁, A₂, A₃, A₄, A₅, A₆ and A₇ is a carbon atom.

In another preferred embodiment, the compound is of formula Ia whereineach of A₁, A₂, A₃, A₄, A₅, A₆ and A₇ is a carbon atom and the phenyl atE substituted with one or more substituents selected from hydrogen,halo, alkyl, cycloalkyl, haloalkyl, hydroxyl, carboxyl, formyloxy,hydroxyalkyl, aldehydo, amino, alkylamino, aminoalkyl, alkylaminoalkyl,dialkylamino, mercapto, alkylmercapto, cyano, cyanoalkyl, nitro, azido,and substituted or unsubstituted groups selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, carbamido, alkoxycarbonyl,alkylaminocarbonyl, aminocarbonyl, alkyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy,phosphonooxyalkyloxy, aminosulfonyl, aminosulfonyloxy,polyethyleneglycoxy, polyethyleneglycoxyalkyl, thioureido, borono,boronoalkyl, boronoalkyloxy, arylalkyloxy, aminocarboxyl,aminocarbonylalkyloxy, aminocarbonylalkylthio, alkylcarbonylamino,aminoalkenylamino, alkylsulfonylamino, phosphono, phosphonothio,phosphonoamino, phosphonoalkyl, phosphonoalkylthio, phosphonoalkylamino,carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxyalkyloxy,carboxyalkylamino, carboxyalkylthio, aminocarbonylthio, hydroxyalkyloxy,hydroxyalkylamino, hydroxyalkylthio, dialkylaminoalkyl, aminoalkylamino,alkylaminoalkylamino, dialkylaminoalkylamino, aminoalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkyloxyaminocarbonyloxy,aminoalkylthio, alkylaminoalkylthio, dialkylaminoalkylthio, and acleavable alcohol prodrug moiety, or any two substituents on E, togetherwith the atoms to which they are attached, form and an optionallysubstituted, saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedcarbocyclic or heterocyclic ring.

In a preferred embodiment of the prior embodiment, the compound above isof the formula Ia, wherein R₉ and R₂₀ are independently selected fromhydrogen and alkyl, or R₉ and R₂₀ together is a carbon-carbon bond.

In a preferred embodiment of the preceeding embodiment, the compound isof formula Ia wherein n is 1; at least one of R₁, R₂, R₃ and R₄ ishydrogen and two of R₁, R₂, R₃ and R₄ are independently selected fromhydrogen, hydroxyl, halo, alkyloxy, alkyl and alkylmercapto; R₅ and R₆together form a carbon-carbon bond; R₇ is hydrogen; and R₈ is selectedfrom hydrogen, alkyl and alkoxy; and, E is phenyl substituted with atleast two alkyloxy groups, each of which may be substituted orunsubstituted.

In a preferred embodiment of the preceeding embodiment, the compound isof formula Ia wherein E is phenyl substituted with at least onetrifluoromethoxy group.

In another preferred embodiment, the compound is a compound of formulaIa of any one or more of any of the aforementioned embodiments eitherindividually or combined, wherein R₂₁ is either —(CH₂)_(n)NR₂₂C(O)X or—(CH₂)_(n)C(O)X.

In a preferred embodiment of the preceeding embodiment, the compound isof formula Ia wherein R₂₁ is —(CH₂)_(n)NR₂₂C(O)X.

In another embodiment, the compound is of formula IIa:

wherein:

each of R₁, R₂, R₃, and R₄ is independently selected from hydrogen,halo, alkyl, hydroxyl, haloalkyl, alkylmercapto, cyano, alkyloxy andhaloalkyloxy;

R₂₁ is selected from —(CH₂)_(n)C(O)X and —(CH₂)_(n)NR₂₂C(O)X;

each of R₅, R₆, R₇, R₈, R₉, R₂₀, and R₂₂ is independently selected fromhydrogen, alkyl, halo, and hydroxyl; or R₅ and R₆ together is acarbon-carbon bond; or R₉ and R₂₀ together is a carbon-carbon bond; orR₆ and R₇ together with the atom to which they are attached form a ring;or R₅ and R₆ together with the atoms to which they are attached, form aring;

n is 1 or 2;

X is selected from aryl, arylalkyl, heterocyclyl and heterocyclylalkyl,or X is NR′R″ where R′ is selected from aryl, arylalkyl, heterocyclyl,and heterocyclylalkyl, where the heterocyclyl of the heterocyclyl andheterocyclylalkyl of the X, and the heterocyclyl of the heterocyclyl andthe heterocyclylalkyl of the R′ when X is NR′R″, is selected from7-membered, 6-membered and 5-membered heterocyclic rings, and the arylof the aryl and arylalkyl, and the heterocyclyl of the heterocyclyl andheterocyclylalkyl, is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy and sulfonamido; R″ is selected from hydrogen, alkyland haloalkyl;

each of R₁₂, R₁₃, R₁₅ and R₁₆ is independently selected from hydrogen,halo, alkyl, cycloalkyl, haloalkyl, alkyloxy, haloalkyloxy, hydroxyl,carboxyl, formyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto,cyano, cyanoalkyl, nitro and azido;

R₁₄ is hydroxyl or is a cleavable alcohol prodrug moiety, or is asubstituted or unsubstituted group selected from alkylsulfinyloxy,alkylsulfonyloxy, carbamate, alkyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy,heterocyclylalkylcarbonyloxy, phosphonooxy, phosphonoalkyloxy,phosphonooxyalkyloxy, aminosulfonyloxy, polyethyleneglycoxy, borono,boronoalkyl, boronoalkyloxy, arylalkyloxy, aminocarbonylalkyloxy,carboxyalkyloxy, hydroxyalkyloxy, aminoalkyloxy, alkylaminoalkyloxy,dialkylaminoalkyloxy and alkyloxyaminocarbonyloxy;

(Z)- or (E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound;

with the proviso that when R₂₁ is —(CH₂)_(n)C(O)X, and R₉ and R₂₀together is a carbon-carbon bond, then at least one of R₅, R₆ and R₇ ishalo, or R₆ and R₇ together with the atom to which they are attachedform a ring, or R₅ and R₆ together with the atoms to which they areattached form a ring, or at least one of R₁, R₂, R₃, and R₄ or at leastone R₁₂, R₁₃, R₁₄, R₁₅ and R₁₆ is haloalkyloxy, or R₁₄ is a substitutedor unsubstituted group selected from polyethyleneglycoxy, borono,boronoalkyl, aminosulfonyloxy and alkyloxyaminocarbonyloxy.

In a preferred embodiment, the compound is of formula IIa wherein X isselected from phenyl, benzyl, heterocyclyl and heterocyclylmethyl, or Xis NR′R″ where R′ is selected from phenyl, benzyl, heterocyclyl andheterocyclylmethyl, where the heterocyclyl of the heterocyclyl and ofthe heterocyclylmethyl of the X, and the heterocyclyl of theheterocyclyl and of the heterocyclylmethyl of the R′ when X is NR′R″, isselected from piperidinyl, oxanyl, thianyl, pyridinyl, pyranyl,thiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl,dithianyl, pyrimidinyl, pyrazinyl, pyridizinyl, oxazinyl, thiazinyl,dioxinyl, dithiinyl, trioxanyl, trithianyl, triazinyl, tetrazinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiaphenyl, pyrrolyl,furanyl, thiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl,dithiolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl,dithiazolyl and tetrazolyl, wherein the phenyl and the phenyl ring ofthe benzyl, and the heterocyclyl of the heterocyclyl andheterocyclylmethyl, is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy and sulfonamide; R″ is selected from hydrogen, alkyland trifluoromethyl.

In a more preferred embodiment, the preceeding compound is of formulaIIa where the heterocyclyl of the heterocyclyl and of theheterocyclylmethyl of the X, and the heterocyclyl of the heterocyclyland of the heterocyclylmethyl of the R′ when X is NR′R″, is selectedfrom furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, dioxolanyl, pyrazolyl, pyridinyl and imidazolyl, and thephenyl and the phenyl ring of the benzyl, and the heterocyclyl of theheterocyclyl and heterocyclylalkyl, is optionally substituted with oneor more of halo, alkyl, haloalkyl, hydroxy, alkyloxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, and carboxamido.

In a further preferred embodiment, the preceeding compound is of formulaIIa wherein X is selected from heterocyclyl and heterocyclylmethyl, or Xis NR′R″ where R′ is selected from heterocyclyl and heterocyclylmethyl,where the heterocyclyl of the heterocyclyl and of the heterocyclylmethylof the X, and the heterocyclyl of the heterocyclyl and of theheterocyclylmethyl of the R′ when X is NR′R″, is selected from furanyl,pyrrolyl, pyridinyl, oxazolyl, thiazolyl, dioxolanyl, imidazolyl,pyrazolyl and thiophenyl, and the heterocyclyl of the heterocyclyl andof the heterocyclylmethyl is optionally substituted with one or more ofhalo, alkyl, trifluoromethyl, hydroxy and methoxy.

In an even more preferred embodiment, the preceeding compound is offormula IIa wherein the heterocyclyl or heterocyclylmethyl is selectedfrom 2-furanyl, 3-furanyl, furan-2-ylmethyl, furan-3-ylmethyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, oxazol-2-ylmethyl,oxazol-4-ylmethyl, oxazol-5-ylmethyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, thiazol-2-ylmethyl, thiazol-4-ylmethyl, thiazol-5-ylmethyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, imidazol-2-ylmethyl,imidazol-4-ylmethyl, imidazol-5-ylmethyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl, pyrazol-3-ylmethyl, pyrazol-4-ylmethyl, pyrazol-5-ylmethyl,2-dioxolanyl, 4-dioxolanyl, dioxolan-2-ylmethyl, anddioxolan-4-ylmethyl; and, R″ is hydrogen.

In a more specific embodiment, the preceeding compound is of formula IIawherein the heterocyclyl or heterocyclylmethyl is selected from2-oxazolyl, oxazol-2-ylmethyl, 2-thiazolyl, thiazol-2-ylmethyl,2-imidazolyl, imidazol-2-ylmethyl, 4-pyrazolyl, pyrazol-4-ylmethyl,2-dioxolanyl and dioxolan-2-ylmethyl.

In an even more specific embodiment, the heterocyclyl orheterocyclylmethyl of the preceeding compound is selected from2-furanyl, 4-pyrazolyl and pyridin-3-ylmethyl.

In a more general embodiment of any one or more of the above embodimentseither individually or combined, the compound is of formula IIa whereineach of R₁, R₂, R₃ and R₄ is independently selected from hydrogen, halo,alkyloxy and alkyl; n is 1; each of R₁₂, R₁₃, R₁₅ and R₁₆ isindependently selected from hydrogen, halo, alkyl, alkyloxy andhaloalkyloxy; R₁₄ is selected from alkyloxy, hydroxyl, and a cleavablealcohol prodrug moiety.

In a preferred embodiment of the preceeding embodiment, the compound isof formula IIa wherein R₂ is selected from halo and alkyloxy; R₁, R₃ andR₄ are hydrogen; two of R₁₂, R₁₃, R₁₅ and R₁₆ are independently selectedfrom hydrogen, alkyloxy and haloalkyloxy.

In a preferred embodiment of the preceeding embodiment, the compound isof formula IIa wherein R₂ is selected from fluoro and methoxy; R₁₂ andR₁₆ are hydrogens,

In a preferred embodiment of the prior embodiment, each of R₁₃ and R₁₅is independently selected from methoxy and trifluoromethoxy; R₁₄ isselected from hydroxyl and methoxy;

In a preferred embodiment of the preceeding embodiment, each of R₁₃ andR₁₅ is methoxy; R₇ is hydrogen; R₈ is alkyl; R₁₄ is hydroxyl; X isselected from heterocyclyl and heterocyclylmethyl, or X is NR′R″ whereR′ is selected from heterocyclyl and heterocyclylmethyl, where theheterocyclyl or the heterocyclylmethyl of the X, and the heterocyclyl orthe heterocyclylmethyl of the R′ when X is NR′R″, is selected from2-furanyl, 4-pyrazolyl and pyridin-3-ylmethyl.

In a preferred embodiment, the compound is a compound of any of theabove embodiments of formula IIa wherein R₉ and R₂₀ together is acarbon-carbon bond.

In yet another preferred embodiment, the compound is a compound of anyof the above embodiments of formula IIa wherein R₅ and R₆ together is acarbon-carbon bond.

In a further preferred embodiment, the compound is a compound of any ofthe above embodiments of formula IIa wherein R₉ and R₂₀ together is acarbon-carbon bond and R₅ and R₆ together is a carbon-carbon bond.

In an additional preferred embodiment, the compound is a compound of anyof the above embodiments of formula IIa, wherein R₂₁ is selected from—(CH₂)_(n)C(O)X or —(CH₂)_(n)NR₂₂C(O)X.

In a different aspect of the preceeding embodiment, R₁₄ cannot beaminosulfonyl when R₂ is —(CH₂)_(n)C(O)X.

In a preferred embodiment of the preceeding embodiment wherein R₂₁ isselected from —(CH₂)_(n)C(O)X or —(CH₂)_(n)NR₂₂C(O)X, the compound is offormula IIa, wherein R₂₁ is —(CH₂)_(n)NR₂₂C(O)X.

In a preferred embodiment of any of the above embodiments of formula Iaand IIa, the compound is selected from:

-   (E)-1-(5-fluoro-1-(4-(hydroxymethyl)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-3-(furan-2-ylmethyl)urea    (1664);-   2-(4-((5-fluoro-3-(3-(furan-2-ylmethyl)ureido)-2-methyl-2,3-dihydro-1H-inden-1-yl)methyl)-2,6-dimethoxyphenyl)acetic    acid (1666);-   (E)-2-((4-((5-fluoro-3-(3-(furan-2-ylmethyl)ureido)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (1668);-   (E)-2-(4-((5-fluoro-2-methyl-3-(3-(pyridin-3-yl)ureido)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1669);-   (E)-2-(4-((5-fluoro-2-methyl-3-(3-(pyridin-3-yl)ureido)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1670);-   2-((4-((3-(3-(1H-pyrazol-5-yl)ureido)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-yl)methyl)-2,6-dimethoxyphenyl)thio)acetic    acid (1671);-   (Z)-2-((4-((5-fluoro-2-methyl-3-(2-oxo-2-(pyridin-3-ylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (1673);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-(pyrazin-2-ylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1674);-   2-(4-((3-(2-((1H-pyrazol-5-yl)amino)-2-oxoethyl)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-yl)methyl)-2,6-dimethoxyphenyl)acetic    acid (1675);-   (Z)-2-(4-((3-(2-(((1H-pyrazol-5-yl)methyl)amino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1676);-   (Z)-1,4-dimethylpiperazin-2-yl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2-methoxyphenyl)amino)acetate    (1677);-   2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-yl)methyl)-2,6-dimethoxyphenyl)acetic    acid (1678);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1679);-   (Z)-3-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)phenyl)propanoic    acid (1680);-   (Z)-2-((2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)amino)acetic    acid (1683);-   (Z)-3-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)propanoic    acid (1685);-   (Z)-2-((4-((3-(2-(benzylamino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (1687);-   (Z)-2-((4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2-methoxyphenyl)amino)acetic    acid (1688);-   (Z)-3-((4-((5-cyano-3-(2-((furan-2-ylmethyl)amino)-2-thioxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)propanoic    acid (1689);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1692);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)acetic    acid (1693);-   (Z)-3-((4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)amino)propanoic    acid (1694);-   (Z)-3-((4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)propanoic    acid (1696);-   (Z)-3-((2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)thio)propanoic    acid (1697);-   (Z)-3-((4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)propanoic    acid (1698);-   (Z)-3-((2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-(phenylamino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)amino)propanoic    acid (1699);-   (Z)-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1732);-   (Z)-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1733);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1734);-   (Z)-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)phenyl)boronic    acid (1735);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1736);-   (Z)-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)boronic    acid (1737);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1738);-   (Z)-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenyl)boronic    acid (1739);-   (Z)-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1740);-   (Z)-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1741);-   (Z)-2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1742);-   (Z)-2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1743);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1744);-   (Z)-2-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-(((1-methyl-H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)phenoxy)acetic    acid (1745);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1746);-   (Z)-2-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenoxy)acetic    acid (1747);-   (Z)-2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1748);-   (Z)-2-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenoxy)acetic    acid (1749);-   (Z)-2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1750);-   (Z)-2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1751);-   (Z)-3-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1752);-   (Z)-3-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1754);-   (Z)-3-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1755);-   (Z)-3-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)phenoxy)propanoic    acid (1756);-   (Z)-3-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1757);-   (Z)-3-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenoxy)propanoic    acid (1758);-   (Z)-3-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1759);-   (Z)-3-(2,6-dimethoxy-4-((5-methoxy-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)phenoxy)propanoic    acid (1760);-   (Z)-3-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1761);-   (Z)-3-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoic    acid (1762);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(furan-2-ylmethyl)acetamide    (1765);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-1-yl)-N-(furan-2-ylmethyl)acetamide    (1767);-   N-(furan-2-ylmethyl)-2-(3-(4-hydroxy-3,5-dimethoxybenzyl)-6-methoxy-2-methyl-1H-inden-1-yl)acetamide    (1768);-   N-(furan-2-ylmethyl)-2-(3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)acetamide    (1769);-   2-(6-cyano-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(furan-2-ylmethyl)acetamide    (1771);-   (Z)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(furan-2-ylmethyl)acetamide    (1772);-   (Z)—N-(furan-2-ylmethyl)-2-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methoxy-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (1773);-   2-(5,6-difluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(furan-2-ylmethyl)acetamide    (1774);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1776);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-1-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1777);-   (Z)-2-(6-cyano-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-((1-methyl-H-pyrrol-2-yl)methyl)acetamide    (1779);-   (Z)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-((1-methyl-H-pyrrol-2-yl)methyl)acetamide    (1780);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1782);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1783);-   (Z)-2-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1784);-   2-(5,6-difluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1785);-   (Z)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1787);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-2-ylmethyl)acetamide    (1789);-   2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-1-yl)-N-(pyridin-2-ylmethyl)acetamide    (1790);-   2-(3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-6-(trifluoromethyl)-1H-inden-1-yl)-N-(pyridin-2-ylmethyl)acetamide    (1791);-   (Z)-2-(6-cyano-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-2-ylmethyl)acetamide    (1792);-   (Z)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyrazin-2-ylmethyl)acetamide    (1793);-   (Z)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)-N-(pyridin-2-ylmethyl)acetamide    (1794);-   N-benzyl-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (1796);-   N-benzyl-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-1-yl)    acetamide (1797);-   (Z)—N-benzyl-2-(3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)acetamide    (1798);-   (Z)—N-benzyl-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (1800);-   (Z)-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1801);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1802);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1803);-   (Z)-4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1804);-   (Z)-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1805);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1806);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1807);-   (Z)-4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1808);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1809);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1810);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1811);-   (Z)-4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1812);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1813);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1814);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1815);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1816);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1817);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1818);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1819);-   (Z)-4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1820);-   (Z)-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (1821);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen phosphate (1822);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (1823);-   (Z)-4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-2,3-dihydro-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (1824);-   (Z)—S-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1831);-   (Z)—S-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1832);-   (Z)—S-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1833);-   (Z)—S-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1834);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1835);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1836);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1837);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1838);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1839);-   (Z)—S-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1840);-   (Z)—S-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    dimethylcarbamothioate (1841);-   (Z)—S-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)    4-methylpiperazine-1-carbothioate (1842);-   (Z)-2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (1849);-   (Z)-3-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)propanoic    acid (1850);-   (Z)-2-(dimethylamino)ethyl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetate    (1851);-   (Z)-2-(dimethylamino)ethyl    3-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)propanoate    (1852);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetate    (1853);-   (Z)-1-methylpiperidin-4-yl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetate    (1854);-   (Z)-2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)-4-guanidinobutanoic    acid (1855);-   (Z)-2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)acetic    acid (1856);-   (Z)-3-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)propanoic    acid (1857);-   (Z)-2-((4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)acetic    acid (1858);-   (Z)-3-((4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)propanoic    acid (1859);-   (Z)-2-(dimethylamino)ethyl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)acetate    (1860);-   (Z)-2-(dimethylamino)ethyl    3-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)propanoate    (1861);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-((4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)acetate    (1862);-   (Z)-2-(dimethylamino)ethyl    2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1863);-   (Z)-2-(dimethylamino)ethyl    3-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1864);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1865);-   (Z)-2-morpholinoethyl    2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1866);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1867);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1868);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-((1-methylpyrrolidin-3-yl)amino)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1869);-   (Z)-1-methylpiperidin-4-yl    2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1870);-   (Z)-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1871);-   (Z)-2-(5-fluoro-1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1872);-   (Z)-(2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1873);-   (Z)-2-(dimethylamino)ethyl    2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1874);-   (Z)-2-(dimethylamino)ethyl    3-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1875);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1876);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1877);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1878);-   (Z)-1-methylpiperidin-4-yl    2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1879);-   (Z)-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (1880);-   (Z)—N-(furan-2-ylmethyl)-2-(1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-5-methoxy-2-methyl-1H-inden-3-yl)acetamide    (1881);-   (Z)-(2-(4-((3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-5-methoxy-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1882);-   (Z)-2-(dimethylamino)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1883);-   (Z)-2-(dimethylamino)ethyl    3-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1884);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1885);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1886);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1887);-   (Z)-1-methylpiperidin-4-yl    2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1888);-   (Z)-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1889);-   (Z)-2-(5-fluoro-1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1890);-   (Z)-(2-(4-((5-fluoro-2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1891);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1892);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (1893);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (1894);-   (Z)-1-methylpiperidin-4-yl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1895);-   (Z)-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (1896);-   (Z)-2-(5-fluoro-1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (1897);-   (Z)-(2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1898);-   (Z)-2-(dimethylamino)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1899);-   (Z)-2-(dimethylamino)ethyl    3-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1900);-   (Z)-2-(dimethylamino)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1901);-   (Z)-2-(dimethylamino)ethyl    3-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1902);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1903);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide    (1904);-   (Z)-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide    (1905);-   (Z)-1-methylpiperidin-4-yl    2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1906);-   (Z)-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide    (1907);-   (Z)-2-(5-fluoro-1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)-N-(pyridin-2-ylmethyl)acetamide    (1908);-   (Z)-(2-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1909);-   (Z)-2-(dimethylamino)ethyl    2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1910);-   (Z)-2-(dimethylamino)ethyl    3-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)propanoate    (1911);-   (Z)-2-(4-methylpiperazin-1-yl)ethyl    2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1912);-   (Z)—N-benzyl-2-(1-(3,5-dimethoxy-4-(2-oxo-2-(piperidin-4-ylamino)ethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamide    (1913);-   (Z)—N-benzyl-2-(1-(3,5-dimethoxy-4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamide    (1914);-   (Z)-1-methylpiperidin-4-yl    2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetate    (1915);-   (Z)—N-benzyl-2-(1-(4-(2-(dimethylamino)ethoxy)-3,5-dimethoxybenzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)acetamide    (1916);-   (Z)—N-benzyl-2-(5-fluoro-1-(4-(2-hydroxyethoxy)-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)acetamide    (1917);-   (Z)-(2-(4-((3-(2-(benzylamino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (1918);-   (Z)-2-(2-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-5H-cyclopenta[b]pyridin-7-yl)-N-(furan-2-ylmethyl)acetamide    (1965);-   (Z)-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-7H-cyclopenta[b]pyridin-5-yl)-N-(furan-2-ylmethyl)acetamide    (1966);-   (Z)-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-7H-cyclopenta[c]pyridin-5-yl)-N-(furan-2-ylmethyl)acetamide    (1967);-   2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzyl)-6-methyl-7H-cyclopenta[c]pyridin-5-yl)-N-(furan-2-ylmethyl)acetamide    (1968);-   (Z)—N-(furan-2-ylmethyl)-2-(7-(4-hydroxy-3,5-dimethoxybenzylidene)-3-methoxy-6-methyl-7H-cyclopenta[b]pyridin-5-yl)acetamide    (1969);-   (E)-2-(7-(4-hydroxy-3,5-dimethoxybenzylidene)-3-methoxy-7H-pyrrolo[3,4-b]pyridin-5-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1970);-   2-(3-cyano-7-(4-hydroxy-3,5-dimethoxybenzyl)-6-methyl-5H-cyclopenta[c]pyridin-5-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1971);-   (Z)—N-(furan-2-ylmethyl)-2-(5-(4-hydroxy-3,5-dimethoxybenzylidene)-3-methoxy-6-methyl-5H-cyclopenta[c]pyridin-7-yl)acetamide    (1972);-   (Z)-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-7H-cyclopenta[c]pyridin-5-yl)-N-(pyridin-4-ylmethyl)acetamide    (1973);-   (Z)-2-(1-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-5H-cyclopenta[c]pyridin-7-yl)-N-(pyridin-2-ylmethyl)acetamide    (1974);-   (E)-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-yl)-N-(pyridin-3-ylmethyl)acetamide    (1975);-   (E)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methylisoindolin-1-yl)-N-(pyridin-3-ylmethyl)acetamide    (1976);-   (E)-2-(2-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)-N-(pyridin-3-ylmethyl)acetamide    (1978);-   (Z)-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-7H-cyclopenta[c]pyridin-5-yl)-N-(pyridin-2-ylmethyl)acetamide    (1979);-   (Z)-2-(2-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-5H-cyclopenta[b]pyrazin-7-yl)-N-(pyridin-2-ylmethyl)acetamide    (1980);-   (Z)—N-benzyl-2-(2-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-5H-cyclopenta[b]pyridin-7-yl)acetamide    (1981);-   (Z)—N-benzyl-2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-7H-cyclopenta[b]pyridin-5-yl)acetamide    (1982);-   (E)-N-benzyl-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-3H-pyrrolo[3,4-c]pyridin-1-yl)acetamide    (1983);-   (E)-N-benzyl-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-yl)acetamide    (1984);-   (E)-1-benzyl-3-(3-fluoro-5-(4-hydroxy-3,5-dimethoxybenzylidene)-6-methyl-5H-cyclopenta[c]pyridin-7-yl)urea    (1985);-   2-(3-fluoro-7-(4-hydroxy-3,5-dimethoxybenzyl)-6-methyl-5H-cyclopenta[b]pyridin-5-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1986);-   (E)-2-(6-fluoro-3-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methylisoindolin-1-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1987);-   (E)-2-(4,6-difluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-3-yl)-N-((1-methyl-1H-pyrrol-2-yl)methyl)acetamide    (1988);-   (Z)-2-(4-((2-fluoro-7-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-5H-cyclopenta[b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1989);-   (Z)-2-(4-((3-fluoro-5-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-7H-cyclopenta[c]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1990);-   (Z)-2-(4-((3-fluoro-5-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1991);-   (Z)-2-(4-((3-fluoro-7-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1992);-   2-(4-((6-fluoro-1-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-1H-pyrrolo[3,4-c]pyridin-3-yl)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1993);-   (E)-2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-1H-isoindol-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1994);-   (E)-2-(2,6-dimethoxy-4-((2-methyl-3-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-5-(trifluoromethyl)isoindolin-1-ylidene)methyl)phenoxy)acetic    acid (1995);-   (E)-2-(4-((5-fluoro-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methylisoindolin-1-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1996);-   2-(4-((6-fluoro-1-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-1H-isoindol-3-yl)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1997);-   2-(4-((2-fluoro-7-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-7H-pyrrolo[3,4-b]pyridin-5-yl)methyl)-2,6-dimethoxyphenoxy)acetic    acid (1998);-   (E)-2-((4-((5-cyano-3-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methylisoindolin-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (1999);-   (Z)-2-(4-((2-fluoro-6-methyl-7-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-5H-cyclopenta[b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2000);-   (Z)-2-(4-((5-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-3-methoxy-6-methyl-7H-cyclopenta[c]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2001);-   (Z)-2-(4-((3-fluoro-6-methyl-5-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2002);-   (Z)-2-(4-((3-fluoro-6-methyl-7-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2003);-   (Z)-2-(4-((5-(2-(benzylamino)-2-oxoethyl)-3-bromo-6-methyl-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2004);-   (E)-2-(4-((7-(2-(benzylamino)-2-oxoethyl)-2-fluoro-5H-pyrrolo[3,4-b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2005);-   (Z)-2-(2,6-dimethoxy-4-((3-methoxy-6-methyl-5-(2-oxo-2-((pyridin-4-ylmethyl)amino)ethyl)-7H-cyclopenta[c]pyridin-7-ylidene)methyl)phenoxy)acetic    acid (2006);-   (Z)-2-(4-((3-fluoro-6-methyl-5-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2007);-   (Z)-2-(4-((1,3-difluoro-6-methyl-7-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2008);-   (Z)-(4-((2-fluoro-7-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-5H-cyclopenta[b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2009);-   (Z)-(4-((3-fluoro-5-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-7H-cyclopenta[c]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2010);-   (Z)-(4-((3-fluoro-5-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2011);-   (Z)-4-((3-fluoro-7-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-6-methyl-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen borate (2012);-   (4-((6-fluoro-1-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-1H-pyrrolo[3,4-c]pyridin-3-yl)methyl)-2,6-dimethoxyphenyl)boronic    acid (2013);-   (E)-4-((5-fluoro-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-isoindol-1-ylidene)methyl)-2,6-dimethoxyphenyl    dihydrogen borate (2014);-   (E)-2-(6-chloro-3-(3,5-dimethoxy-4-sulfamoylbenzylidene)-2-methylisoindolin-1-yl)-N-(furan-2-ylmethyl)acetamide    (2015);-   (Z)-2-(4-((3-chloro-5-(3-(furan-2-ylmethyl)ureido)-6-methyl-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2016);-   2-(4-((3-fluoro-5-(3-(furan-2-ylmethyl)ureido)-6-methyl-5H-cyclopenta[c]pyridin-7-yl)methyl)-2,6-dimethoxyphenoxy)acetic    acid (2017);-   2-((4-((2-fluoro-7-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-7H-pyrrolo[3,4-b]pyridin-5-yl)methyl)-2-methoxyphenyl)amino)acetic    acid (2018);-   (4-((6-fluoro-1-(2-((furan-2-ylmethyl)amino)-2-oxoethyl)-2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-3-yl)methyl)-2,6-dimethoxyphenyl)boronic    acid (2019);-   (Z)-2-((4-((2-fluoro-6-methyl-7-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-5H-cyclopenta[b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (2020);-   (Z)-2-((4-((5-(3-(furan-2-ylmethyl)ureido)-3-methoxy-6-methyl-7H-cyclopenta[c]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (2021);-   (Z)-(2-(4-((3-fluoro-6-methyl-5-(2-(((1-methyl-1H-pyrrol-2-yl)methyl)amino)-2-oxoethyl)-7H-cyclopenta[b]pyridin-7-ylidene)methyl)-2,6-dimethoxyphenoxy)ethyl)boronic    acid (2022);-   (Z)-2-((4-((3-fluoro-6-methyl-7-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (2023);-   (Z)-2-((5-((5-(3-(benzylamino)-3-oxopropyl)-3-methoxy-6-methyl-5H-cyclopenta[b]pyridin-7(6H)-ylidene)methyl)-2-methoxyphenyl)amino)acetic    acid (2024);-   (E)-2-((4-((7-(2-(benzylamino)-2-oxoethyl)-2-fluoro-5H-pyrrolo[3,4-b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl)amino)acetic    acid (2025);-   (Z)-2-((2,6-dimethoxy-4-((3-methoxy-6-methyl-5-(2-oxo-2-((pyridin-4-ylmethyl)amino)ethyl)-7H-cyclopenta[c]pyridin-7-ylidene)methyl)phenyl)amino)acetic    acid (2026);-   (Z)-2-((2,6-dimethoxy-4-((3-methoxy-6-methyl-5-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-7H-cyclopenta[b]pyridin-7-ylidene)methyl)phenyl)amino)acetic    acid (2027);-   (Z)-2-((4-((3-fluoro-6-methyl-7-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-5H-cyclopenta[c]pyridin-5-ylidene)methyl)-2-methoxyphenyl)amino)acetic    acid (2028);-   (E)-2-((4-((7-(2-(benzylamino)-2-oxoethyl)-2-fluoro-5H-pyrrolo[3,4-b]pyridin-5-ylidene)methyl)-2,6-dimethoxyphenyl)thio)acetic    acid (2029);-   (Z)-3-(2,6-dimethoxy-4-((3-methoxy-6-methyl-5-(2-oxo-2-((pyridin-4-ylmethyl)amino)ethyl)-7H-cyclopenta[c]pyridin-7-ylidene)methyl)phenyl)propanoic    acid (2030);-   (Z)-2-(2,6-dimethoxy-4-((3-methoxy-6-methyl-5-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-7H-cyclopenta[b]pyridin-7-ylidene)methyl)phenyl)acetic    acid (2031);-   (((4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)-1H-inden-1-yl)methyl)-2,6-dimethoxyphenyl)amino)methyl)phosphonic    acid (2042);-   (Z)-(((4-((5-fluoro-2-methyl-3-(2-oxo-2-(pyrazin-2-ylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)methyl)phosphonic    acid (2043);-   (Z)-(((4-((5-fluoro-2-methyl-3-(2-oxo-2-((pyridin-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)methyl)phosphonic    acid (2044);-   (Z)-(2-((4-((3-(2-((1H-pyrazol-5-yl)amino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)amino)ethyl)phosphonic    acid (2047);-   (Z)-(2-((4-((5-fluoro-2-methyl-3-(2-oxo-2-(pyridin-3-ylamino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)thio)ethyl)phosphonic    acid (2048);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-((oxazol-2-ylmethyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2066);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-((oxazol-4-ylmethyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2067);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-((oxazol-5-ylmethyl)amino)-2-oxoethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2068);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2069);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((thiazol-4-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2070);-   (Z)-(4-((5-fluoro-2-methyl-3-(2-oxo-2-((thiazol-5-ylmethyl)amino)ethyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2071);-   (Z)-(4-((3-(2-(((1H-imidazol-5-yl)methyl)amino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2072);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1-methyl-1H-pyrrole-2-carboxamide    (2085);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrrole-2-carboxamide    (2086);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrrole-3-carboxamide    (2087);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1-methyl-1H-pyrrole-3-carboxamide    (2088);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)furan-3-carboxamide    (2089);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)furan-2-carboxamide    (2090);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(furan-3-yl)acetamide    (2092);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-imidazole-4-carboxamide    (2093);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1H-imidazol-5-yl)acetamide    (2094);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1H-pyrazol-5-yl)acetamide    (2095);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-3-yl)acetamide    (2096);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-2-yl)acetamide    (2097);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-4-yl)acetamide    (2098);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)nicotinamide    (2100);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-phenylacetamide    (2101);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)benzamide    (2102);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-5-yl)acetamide    (2103);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-2-yl)acetamide    (2104);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-4-yl)acetamide    (2105);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(thiazol-5-yl)acetamide    (2106);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-4-carboxamide    (2107);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-5-carboxamide    (2108);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-2-carboxamide    (2109);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-5-yl)acetamide    (2110);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-3-yl)acetamide    (2111);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-4-yl)acetamide    (2112);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)isoxazole-5-carboxamide    (2113);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyrazin-2-yl)acetamide    (2114);-   (Z)-(4-((3-((1H-imidazole-4-carboxamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2115);-   (Z)-4-((3-((1H-imidazole-2-carboxamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (2116);-   (Z)-(4-((3-((2-(1H-imidazol-2-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2117);-   (Z)-4-((3-((2-(1H-imidazol-5-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    ethylcarbamate (2118);-   (Z)-(4-((3-((2-(1H-pyrazol-5-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2119);-   (Z)-4-((5-fluoro-2-methyl-3-((oxazole-4-carboxamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    ethylcarbamate (2120);-   (Z)-4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (2121);-   (Z)-4-((5-fluoro-2-methyl-3-((oxazole-2-carboxamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    dimethylcarbamate (2122);-   (Z)-(4-((5-fluoro-3-((2-(isoxazol-4-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2123);-   (Z)-(4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2124);-   (Z)-4-((5-fluoro-2-methyl-3-((2-phenylacetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (2125);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (2126);-   (Z)-4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    4-methylpiperazine-1-carboxylate (2127);-   (Z)-4-((3-((2-(1H-imidazol-5-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (2128);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(thiazol-5-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    morpholine-4-carboxylate (2129);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    ethylcarbamate (2130);-   (Z)-(4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2131);-   (Z)-(4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2132);-   (Z)-(4-((5-fluoro-2-methyl-3-((2-(1-methyl-1H-pyrrol-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2133);-   (Z)-(4-((5-fluoro-3-((furan-2-carboxamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2134);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2135);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(oxazol-5-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2136);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(oxazol-4-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2137);-   (Z)-4-((5-fluoro-2-methyl-3-((2-phenylacetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2138);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2139);-   (Z)-4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2140);-   (Z)-4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2141);-   (Z)-4-((5-fluoro-2-methyl-3-((2-(1-methyl-1H-pyrrol-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl    [1,4′-bipiperidine]-1′-carboxylate (2142);-   (E)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)methyl)-2-(furan-2-yl)acetamide    (2143);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)-N-(furan-2-ylmethyl)acetamide    (2144);-   (E)-N-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)-2-(furan-2-yl)acetamide    (2145);-   (E)-5-fluoro-N-(furan-2-ylmethyl)-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-indene-2-carboxamide    (2146);-   (E)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)methyl)-2-(1-methyl-1H-pyrrol-2-yl)acetamide    (2147);-   (E)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)methyl)-2-phenylacetamide    (2149);-   (E)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)methyl)-2-(pyridin-2-yl)acetamide    (2151);-   (E)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)methyl)-2-(isoxazol-5-yl)acetamide    (2153);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-1H-inden-2-yl)-N-(oxazol-5-ylmethyl)acetamide    (2154);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(oxazol-2-ylmethyl)acetamide    (2155);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(oxazol-5-ylmethyl)acetamide    (2156);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(oxazol-4-ylmethyl)acetamide    (2157);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(thiazol-2-ylmethyl)acetamide    (2158);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(thiazol-5-ylmethyl)acetamide    (2159);-   (Z)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)-N-(thiazol-4-ylmethyl)acetamide    (2160);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3-methoxy-5-(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(oxazol-5-ylmethyl)acetamide    (2161);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3-(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(oxazol-4-ylmethyl)acetamide    (2162);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-bis(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(oxazol-2-ylmethyl)acetamide    (2163);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3,5-bis(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(thiazol-2-ylmethyl)acetamide    (2164);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3-methoxy-5-(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(thiazol-5-ylmethyl)acetamide    (2165);-   (Z)-2-(5-fluoro-1-(4-hydroxy-3-(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)-N-(thiazol-4-ylmethyl)acetamide    (2166);-   (Z)—N-((1,3-dioxolan-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3,5-bis(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)acetamide    (2167);-   (Z)—N-((1,3-dioxolan-2-yl)methyl)-2-(5-fluoro-1-(4-hydroxy-3-(trifluoromethoxy)benzylidene)-2-methyl-1H-inden-3-yl)acetamide    (2168);-   (Z)-2-(1,3-dioxolan-2-yl)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)acetamide    (2174);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(2-methyl-1,3-dioxolan-4-yl)acetamide    (2175);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(thiazol-2-yl)acetamide    (2176);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1,3-oxathiolan-2-yl)acetamide    (2179);-   (Z)—N-((1,3-dioxolan-2-yl)methyl)-2-(1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-5-(trifluoromethoxy)-1H-inden-3-yl)acetamide    (2181);-   (Z)-(4-((3-(2-(((1,3-dioxolan-2-yl)methyl)amino)-2-oxoethyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronic    acid (2182);-   (Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrazole-4-carboxamide    (2183);-   2-(5-fluoro-1-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (2184);-   N-benzyl-2-(5-fluoro-1-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-1H-inden-3-yl)acetamide    (2185);-   N-(furan-2-ylmethyl)-2-(2,3,6-trifluoro-3-(1-(4-hydroxy-3,5-dimethoxyphenyl)ethyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (2186);-   N-benzyl-2-(2,3,6-trifluoro-3-(1-(4-hydroxy-3,5-dimethoxyphenyl)ethyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (2187);-   2-(1,5-difluoro-1-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (2188);-   N-benzyl-2-(1,5-difluoro-1-(4-hydroxy-3,5-dimethoxybenzyl)-2-methyl-1H-inden-3-yl)acetamide    (2189);-   2-(1-(difluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (2190);-   N-benzyl-2-(1-(difluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-5-fluoro-2-methyl-1H-inden-3-yl)acetamide    (2191);-   2-(1,5-difluoro-1-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (2192);-   N-benzyl-2-(1,5-difluoro-1-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-1H-inden-3-yl)acetamide    (2193);-   2-(2,5′-difluoro-2-(4-hydroxy-3,5-dimethoxyphenyl)-2′-methylspiro[cyclopropane-1,1′-inden]-3′-yl)-N-(furan-2-ylmethyl)acetamide    (2194);-   N-benzyl-2-(2,5′-difluoro-2-(4-hydroxy-3,5-dimethoxyphenyl)-2′-methylspiro[cyclopropane-1,1′-inden]-3′-yl)acetamide    (2195);-   N-(furan-2-ylmethyl)-2-(1,2,3,6-tetrafluoro-3-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (2196);-   N-benzyl-2-(1,2,3,6-tetrafluoro-3-(fluoro(4-hydroxy-3,5-dimethoxyphenyl)methyl)-2-methyl-2,3-dihydro-1H-inden-1-yl)acetamide    (2197);-   2-(5-fluoro-1-(1-(4-hydroxy-3,5-dimethoxyphenyl)cyclopropyl)-2-methyl-1H-inden-3-yl)-N-(furan-2-ylmethyl)acetamide    (2198);-   N-benzyl-2-(5-fluoro-1-(1-(4-hydroxy-3,5-dimethoxyphenyl)cyclopropyl)-2-methyl-1H-inden-3-yl)acetamide    (2199);-   (Z)-2-(1-(3,5-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)-5-fluoro-2-methyl-1H-inden-3-yl)-N-(pyridin-3-ylmethyl)acetamide    (2200)

(Z)- or (E)-isomer thereof, epimer, diastereomer or rotamer thereof,pharmaceutically acceptable salt or prodrug thereof.

In a preferred embodiment of the preceeding embodiment, the compound isselected from compounds numbered above as 1732, 1733, 1734, 1735, 1736,1737, 1738, 1739, 1740, 1741, 2066, 2067, 2068, 2069, 2070, 2071, 2072,2182, 2200, 1765, 1767, 1768, 1769, 1771, 1772, 1773, 1774, 1776, 1777,1779, 1780, 1782, 1783, 1784, 1785, 1787, 1789, 1790, 1791, 1792, 1793,1794, 1796, 1797, 1798, 1800, 1801, 1802, 1803, 1804, 1805, 1806, 1807,1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817, 1818, 1819,1820, 1821, 1822, 1823, 1824, 2184, 2185, 2186, 2187, 2188, 2189, 2190,2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2085, 2086, 2087,2088, 2089, 2090, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2100, 2101,2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109, 2110, 2111, 2112, 2113,2114, 2115, 2116, 2117, 2119, 2120, 2121, 2122, 2123, 2124, 2125, 2126,2127, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138,2139, 2140, 2141, 2142, 2143, 2144, 2145, 2146, 2147, 2149, 2151, 2153,2174, 2175, 2176, 2179, 2183, 2155, 2156, 2157, 2158, 2159, 2160, 2161,2162, 2163, 2164, 2165, 2166, 2167, 2168 and 2181.

In a more preferred embodiment of the above embodiment, the compound isselected from compounds numbered as 1732, 1733, 1734, 1735, 1736, 1737,1738, 1739, 1740, 1741, 2066, 2067, 2068, 2069, 2070, 2071, 2072, 2182,2200, 1765, 1767, 1768, 1769, 1771, 1772, 1773, 1774, 1776, 1777, 1779,1780, 1782, 1783, 1784, 1785, 1787, 1789, 1790, 1791, 1792, 1793, 1794,1796, 1797, 1798, 1800, 1801, 1802, 1803, 1804, 1805, 1806, 1807, 1808,1809, 1810, 1811, 1812, 1813, 1814, 1815, 1816, 1817, 1818, 1819, 1820,1821, 1822, 1823, 1824, 2184, 2185, 2186, 2187, 2188, 2189, 2190, 2191,2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2085, 2086, 2087, 2088,2089, 2090, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2100, 2101, 2102,2103, 2104, 2105, 2106, 2107, 2108, 2109, 2110, 2111, 2112, 2113, 2114,2115, 2116, 2117, 2119, 2120, 2121, 2122, 2123, 2124, 2125, 2126, 2127,2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138, 2139,2140, 2141, 2142, 2143, 2144, 2145, 2146, 2147, 2149, 2151, 2153, 2174,2175, 2176, 2179 and 2183.

In a more preferred embodiment of the above embodiment, the compound isselected from compounds numbered as 1765, 1767, 1768, 1769, 1771, 1772,1773, 1774, 1776, 1777, 1779, 1780, 1782, 1783, 1784, 1785, 1787, 1789,1790, 1791, 1792, 1793, 1794, 1796, 1797, 1798, 1800, 1801, 1802, 1803,1804, 1805, 1806, 1807, 1808, 1809, 1810, 1811, 1812, 1813, 1814, 1815,1816, 1817, 1818, 1819, 1820, 1821, 1822, 1823, 1824, 2184, 2185, 2186,2187, 2188, 2189, 2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198,2199, 2085, 2086, 2087, 2088, 2089, 2090, 2092, 2093, 2094, 2095, 2096,2097, 2098, 2100, 2101, 2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109,2110, 2111, 2112, 2113, 2114, 2115, 2116, 2117, 2119, 2120, 2121, 2122,2123, 2124, 2125, 2126, 2127, 2128, 2129, 2130, 2131, 2132, 2133, 2134,2135, 2136, 2137, 2138, 2139, 2140, 2141, 2142, 2143, 2144, 2145, 2146,2147, 2149, 2151, 2153, 2174, 2175, 2176, 2179 and 2183.

In a more preferred embodiment of the above embodiment, the compound isselected from compounds numbered as 2184, 2185, 2186, 2187, 2188, 2189,2190, 2191, 2192, 2193, 2194, 2195, 2196, 2197, 2198, 2199, 2085, 2086,2087, 2088, 2089, 2090, 2092, 2093, 2094, 2095, 2096, 2097, 2098, 2100,2101, 2102, 2103, 2104, 2105, 2106, 2107, 2108, 2109, 2110, 2111, 2112,2113, 2114, 2115, 2116, 2117, 2119, 2120, 2121, 2122, 2123, 2124, 2125,2126, 2127, 2128, 2129, 2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137,2138, 2139, 2140, 2141, 2142, 2143, 2144, 2145, 2146, 2147, 2149, 2151,2153, 2174, 2175, 2176, 2179 and 2183.

In a more preferred embodiment of the above embodiment, the compound isselected from compounds numbered as 2085, 2086, 2087, 2088, 2089, 2090,2092, 2093, 2094, 2095, 2096, 2097, 2098, 2100, 2101, 2102, 2103, 2104,2105, 2106, 2107, 2108, 2109, 2110, 2111, 2112, 2113, 2114, 2115, 2116,2117, 2119, 2120, 2121, 2122, 2123, 2124, 2125, 2126, 2127, 2128, 2129,2130, 2131, 2132, 2133, 2134, 2135, 2136, 2137, 2138, 2139, 2140, 2141,2142, 2143, 2144, 2145, 2146, 2147, 2149, 2151, 2153, 2174, 2175, 2176,2179 and 2183.

In a most preferred embodiment, the compound of the invention is offormula IIa selected from compounds numbered as 1732, 1736, 1740, 1765,1767, 1772, 1782, 1783, 1796, 1797, 2066, 2069, 2090, 2096, 2155, 2158,2163, 2164, 2167, 2168, 2174, 2176, 2179, 2181, 2182, 2183, 2190, 2191,2192, 2193, 2194 and 2195.

Chemical structures of all the the above-named and numbered compoundsare:

The present invention also provides a pharmaceutical compositioncomprising a compound of formula Ia or IIa, or pharmaceuticallyacceptable salt or prodrug thereof, and a pharmaceutically acceptablecarrier.

In an embodiment, the the pharmaceutical composition further includes atleast one therapeutic agent, which is not a compound of formula Ia orIIa or salt or prodrug thereof.

The present invention further provides a method of therapeuticallytreating a human or nonhuman mammalian patient with cancer comprisingadministering to said patient an effective amount of at least onecompound of Ia or IIa, or pharmaceutically acceptable salt or prodrugthereof, either alone or in combination with at least one additionalagent which is selected from an anticancer agent and radiation.

In an embodiment, the patient with cancer is a patient in whom thecancer is one or more of the following types of cancer: pancreaticcancer, lung cancer, colorectal cancer, melanoma, ovarian cancer, renalcancer, prostate cancer, head and neck cancer, endocrine cancer, uterinecancer, breast cancer, sarcoma cancer, gastric cancer, hepatic cancer,esophageal cancer, central nervous system cancer, brain cancer, hepaticcancer, germline cancer, lymphoma, and leukemia.

In a preferred embodiment, the cancer is selected from pancreaticcancer, colorectal cancer, and lung cancer.

In another preferred embodiment, the cancer is drug-resistant orradiation-resistant.

The present invention further provides a method of treating a human ornonhuman mammalian patient with a disease or condition treatable by theinhibition of one or more neoplastic or cancerous process, which methodcomprises administering to a patient in need thereof an effective amountof at least one neoplastic or cancerous inhibitory compound of formulaIa or IIa, or pharmaceutically acceptable salt or prodrug thereof,either alone or in combination with at least one therapeutic agent whichis not a compound of formula Ia or IIa or salt or prodrug thereof.

In a preferred embodiment, the neoplastic or cancerous process isselected from growth, proliferation, survival, metastasis, drugresistance and radiation resistance of a tumor cell.

In another preferred embodiment, the at least one therapeutic agent thatis not a compound of formula Ia or IIa is selected from an anticancerdrug and radiation.

The present invention additionally provides a compound of formula Ia orIIa, or pharmaceutically acceptable salt or prodrug or pharmaceuticalcomposition thereof, for use in the treatment or prophylaxis of a humanor nonhuman mammalian patient with cancer.

In a preferred embodiment, the invention provides a compound of formulaIa or IIa, or pharmaceutically acceptable salt or prodrug orpharmaceutical composition thereof, for use in treating a patient with acancer selected from pancreatic cancer, lung cancer, colorectal cancer,melanoma, ovarian cancer, renal cancer, prostate cancer, head and neckcancer, endocrine cancer, uterine cancer, breast cancer, sarcoma cancer,gastric cancer, hepatic cancer, esophageal cancer, central nervoussystem cancer, brain cancer, hepatic cancer, germline cancer, lymphoma,and leukemia.

In a more preferred embodiment, the invention provides a compound offormula Ia or IIa, or pharmaceutically acceptable salt or prodrug orpharmaceutical composition thereof, for use in treating a patientwherein the cancer is pancreatic cancer, colorectal cancer, or lungcancer.

In another preferred embodiment, the compound of formula Ia or IIa,pharmaceutically acceptable salt or prodrug or pharmaceuticalcomposition thereof, is for use in treating a patient with cancerwherein the cancer is drug-resistant or radiation-resistant.

In a further embodiment, the compound of formula Ia or IIa, or apharmaceutically acceptable salt or prodrug or pharmaceuticalcomposition thereof, is for use in the treatment or prophylaxis of adisease or condition treatable by the inhibition of one or moreneoplastic or cancerous process in a human or nonhuman mammalianpatient, either alone or in combination with at least one therapeuticagent which is not a compound of formula Ia or IIa or salt or prodrugthereof.

In a preferred embodiment, the compound or a pharmaceutically acceptablesalt or prodrug or pharmaceutical composition thereof, is for use ininhibiting a neoplastic or cancerous process selected from growth,proliferation, survival, metastasis, drug resistance and radiationresistance of a tumor cell.

In another embodiment, the anticancer compounds provided by theinvention include Ras-inhibitory compounds. A Ras-inhibitory compoundcan be identified from one or more compounds of formulas Ia and IIa byan assay of Ras inhibition. Some representative assays of selective Rasinhibition are illustrated in the examples that follow herein. As usedherein, the terminology selective “Ras inhibition” means selective,preferential or specific inhibition of aberrant Ras-mediated cellularprocesses, such as, for example, accelerated or aberrant cell growth,proliferation, survival, and invasiveness, relative to these processesin cells or tissues with normal or non-aberrant Ras and Ras-mediatedprocesses. Experimentally, selective Ras inhibition can be shown, forexample, by determining the ratio (numerator/denominator) of a givencompound's potency (e.g., IC50) to inhibit the growth of cells with“normal” or “wild-type” Ras (numerator) relative to that of cells withmutated and/or activated Ras (denominator). The terminology used hereinfor such an experimentally determined ratio is “selectivity” or“selectivity index”, which is further denoted by showing the respectivecell types used to determine the numerical ratio (e.g., HT-29/A549;Caco-2/SW-480; HT-29/SW-480; HT-29/CCT-116). For a given compound, a“selectivity” value or “selectivity index” of greater than 1 (one),preferably greater than 10 (ten), more preferably greater than 100 (onehundred) and even more preferably greater than 1000 (one thousand)indicates said compound selectively inhibits hyperactive Ras and/orRas-mediated cellular functions, such as those which may drive oraccelerate cancer cell growth, proliferation, metastasis, resistance todrugs or radiation, and the like.

In another preferred embodiment of the present invention, theaforementioned assay of Ras inhibition employs one or more isogenic cellline pair(s), wherein both of the lines share the same geneticbackground except that one of the lines (“mutant line”) contains one ormore mutated or hyperactive ras gene(s), Ras protein(s) and/or aberrantRas-mediated biological process(es), and the other line (“normal line”)lacks such mutation(s) or aberrant function(s).

In a further preferred embodiment of the present invention, the assayemploying isogenic cell line(s), enables the determination andcalculation of a Ras-Inhibitory Specificity Index (RISI). Oneexperimental approach to determination of such a RISI may, for example,comprise determining the ratio of the concentration of a compoundproducing a specified effect on the normal line or Ras-deficient line,such as, for example, 50% growth inhibition in a specified period oftime, divided by the concentration of the same compound producing thesame specified effect (e.g., 50% growth inhibition in the same specifiedperiod of time) on the mutant line.

Whereas in the aforementioned approach, the 50% growth inhibition valuesmay be obtained by testing the compound against both normal and mutantcell lines at multiple concentrations over a specified concentrationrange, for example 10 nM-10,000 nM, an alternate, more streamlinedapproach to determining a RISI value could comprise measuring the ratioof percentage growth inhibition in a given period of time by a specifiedsingle concentration of the compound, for example 250 nM, selected fromwithin a range of concentrations, for example from within a range of 10nM-10,000 nM, against the Ras mutant relative to the normal or Rasdeficient cell line. This approach may be generally more applicable tolarger-scale or preliminary screening of groups of individual compoundsor mixtures thereof to obtain a preliminary or screening RISI, whereas aRISI determined using concentration ranges to determine 50% growthinhibition values may be more precise. A RISI value obtained for a givencompound by either approach may be less than, equal to or greater than 1(one), and a RISI value of greater than 1 (one) indicates said compoundselectively inhibits Ras or Ras-mediated cellular functions.

In a highly preferred embodiment of the present invention, the employedassay of Ras inhibition enables identification of a compound from one ormore compounds of formulas Ia or IIa having a RISI of greater than 1,preferably greater than 10, more preferably greater than 100, and evenmore preferably greater than 1000.

The present invention yet further provides a pharmaceutical compositioncomprising a therapeutically effective amount of Ras-inhibitory activityfrom one or more Ras-inhibitory compound(s) of formula Ia or IIa, orpharmaceutically acceptable salt(s) or prodrug(s) thereof, alone or incombination with at least one therapeutic agent which is not a compoundof formula Ia or IIa, or salt or prodrug thereof. The therapeuticallyeffective amount can be that amount provided by a Ras-inhibiting and/ora disease-process inhibiting effective amount, such as an anticancereffective amount, of a compound of formula Ia or IIa, orpharmaceutically acceptable salt or prodrug thereof.

In addition, the present invention provides a method of therapeuticallyor prophylactically treating a condition treatable by the inhibition ofRas-mediated biological processes including, for example, tumor cellgrowth, proliferation, survival, invasion and metastasis, as well asresistance to chemotherapy, other molecularly targeted therapeutics, andradiation; and, a method of therapeutically or prophylactically treatingcancers harboring hyperactive or mutant Ras. These methods compriseadministering a therapeutically or prophylactically effective amount ofRas-inhibiting activity from at least one Ras-inhibitory compound, orpharmaceutically acceptable salt or prodrug thereof, of formula Ia orIIa.

For example, the disease or condition treatable by the inhibition of oneor more Ras-mediated biological process is cancer, neurofibromatosis, orCostello syndrome. In an embodiment, the Ras-mediated biological processis selected from growth, proliferation, survival, metastasis, drugresistance and radiation resistance of a tumor cell.

In an embodiment of the above method, the patient is pre-selected byutilizing an assay of the patient's tissue, blood or tumor for anabnormal, mutant or hyperactive ras gene or Ras protein, or an aberrantRas-mediated biological process.

In an embodiment, the patient's tissue, blood or tumor contains anabnormal, mutant or hyperactive ras gene or Ras protein, or aberrantRas-mediated biological process.

The compounds in the present invention also can be in the form of apharmaceutically acceptable salt, which may include, for example, thesalt of one or more acidic substituents (e.g. a carboxylic salt, asulfonic acid salt, and the like) and the salt of one or more basicsubstituents (e.g. the salt of an amine, and the like). Suitable saltsof acidic substituents include, for example, metal salts (e.g. sodiumsalts, potassium salts, magnesium salts, zinc salts, and the like) andammonium salts (e.g., NH4+ salts, alkylammonium salts, quaternaryammonium salts, and the like). Suitable salts of basic substituentsinclude, for example, acid addition salts (e.g., hydrochloride salts,hydrobromide salts, carboxylate salts (e.g., acetate salts), sulfatesalts, sulfonate salts (e.g., mesylate salts), phosphate salts,quaternary ammonium salts, and the like.

A compound of the present invention can also be provided as a prodrug,which is a modified drug derivative or drug precursor compound that mayhave desired biological activity that is the same, similar or preferableto the original drug. Typically, the modified drug is inactive or lessthan fully active until it is converted in the body through a normalmetabolic process, such as, for example, conversion of a promoiety to ahydroxyl group, or hydrolysis of an ester or amide form of the drug, tothe active drug. A prodrug may be selected and used instead of theparent drug because, for example, in its prodrug form it is less toxic,and/or may have better absorption, distribution, metabolism andexcretion (ADME) characteristics, and the like, than the parent drug. Aprodrug might also be used to improve how selectively the drug interactswith cells or processes that are not its intended target. This approachmay be employed particularly, for example, to prevent or decreaseadverse effects, especially in cancer treatments, which may beespecially prone to having severe unintended and undesirable sideeffects.

The term “prodrug” denotes a derivative of a compound, which derivative,when administered to warm-blooded animals, e.g. humans, is convertedinto the desired active compound (drug). For example, the enzymaticand/or chemical hydrolytic cleavage of a derivative compound of thepresent invention occurs in such a manner that the proven drug form isreleased, and the moiety or moieties split off remain nontoxic or aremetabolized so that nontoxic metabolites are produced. For example, acarboxylic acid group can be esterified, e.g., with a methyl group orethyl group to yield an ester. When an ester is administered to asubject, the ester is cleaved, enzymatically or non-enzymatically,reductively, oxidatively, or hydrolytically, to reveal the anionicgroup. An anionic group can be esterified with moieties (e.g.,acyloxymethyl esters) which are cleaved to reveal an intermediatecompound which subsequently decomposes to yield the active compound.

Numerous anticancer drugs used clinically, or that have been or are indevelopment for clinical use, are prodrugs. For example, a prodrug ormasking strategy has been used for anticancer drugs such as etoposide(Schacter, Semin. Oncol. 23: (6 Suppl. 13): 1-7, 1996), irinotecan(Slatter et. al., Drug Metab. Dispos. 28: 423-433, 2000), andcombretastatin-A4 (Pettit et. al., J. Med. Chem. 38: 1666-1672, 1995a;Pettit et al., Anticancer Drug Des. 10: 293-309, 1995b; Kong et. al.,Chem. Biol. 12: 1007-1014, 2005), all of which drugs contain at leastone hydroxyl substituent potentially compromising pharmaceutical utilityin a given situation.

The phosphate prodrug of etoposide is highly water-soluble, yet withessentially identical anticancer efficacy in vivo as the parent drug(Schacter, supra). Irinotecan is a more aqueous-soluble carbamateprodrug of an anticancer active metabolite of the natural product,camptothecin (Slatter et al., supra). Combretastatin-A4 is a naturalproduct (Pettit et al., 1995a) with anticancer properties compromised bythe poor aqueous solubility of the parent compound, leading to thesynthesis of a more aqueous soluble phosphate prodrug (Pettit et al.,1995b).

In another approach to remedying the poor aqueous solubility andmetabolic vulnerability of the phenolic hydroxyl group contained incombretastatin-A4, Kong et al., (supra) made a combretastatin-A4derivative wherein the phenolic hydroxyl was instead a boronic acidgroup (said group having the formula —B(OH)2, also known as a boronogroup, a dihydroxyboranyl group, or a dihydroxyboryl group). Althoughthis was deemed by Kong et. el. (supra) as a “bioisosteric”substitution, other investigators have shown that the boronic acidmoiety in the anticancer drug, bortezomib, is predominantly converted invivo to a hydroxyl group (Pekol et al., Drug Metab. Dispos. 33: 771-777,2005). Thus, the boronic acid moiety can be considered as either abioisosteric substitution for a hydroxyl group, or as a promoiety for invivo conversion to a desired hydroxyl group, for example the hydroxylgroup at R₁₄ of a compound of formula Ia or IIa of the inventiondescribed herein. Such a boronic acid derivative of a compound offormula Ia or IIa can be prepared routinely by methods well-known to oneskilled in the art, for example by adaptation of methodology used byKong et. al. (supra) for replacing a hydroxyl group in combretastatin A4with a borono group. As a more specific example, the phenolic hydroxylgroup at R₁₄ of a compound of the invention (or a related prior-artcompound) can be replaced with a borono group by one skilled in the artusing well-known methods to yield a novel and distinct, medicallyuseful, compound of formula Ia or IIa.

The desired prodrugs can be prepared in situ during the isolation andpurification of the compounds, or by separately reacting the purifiedcompound with a suitable derivatizing agent. For example, hydroxy groupscan be converted into esters via treatment with a carboxylic acid in thepresence of a catalyst. Examples of cleavable alcohol prodrug moietiesinclude substituted or unsubstituted, branched or unbranched alkyl estermoieties, e.g., ethyl esters, alkenyl esters, di-alkylamino alkylesters, e.g., dimethylaminoethyl ester, acylamino alkyl esters, acyloxyalkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenylester, aryl-alkyl esters, e.g., benzyl ester, optionally substituted,e.g., with methyl, halo, or methoxy substituents aryl and aryl-alkylesters, amides, alkyl amides, di-alkyl amides, and hydroxy amides. Asanother example, an alkyloxy group can serve as a prodrug moiety for ahydroxyl group; for instance, an alkoxy group on a phenyl ring can beenzymatically demethylated in vivo to yield a phenolic hydroxyl moiety.

Knowing the disclosures herein, it will be appreciated also that acompound of the present invention can be in the form of a prodrug, andthat such prodrugs can be prepared using reagents and synthetictransformations that are well-known to those having ordinary skill inthe art. The effectiveness of a selected prodrug can be determined usingone or more analytical methods (e.g. pharmacokinetics, bioassays, invivo efficacy studies, and the like) that are well-known to those ofordinary skill in the art.

More specifically, a prodrug having a formula of Ia or IIa may beprepared using routine chemical procedures, such as the exemplaryprocedures described herein. For instance, any one of R₁, R₂, R₃, R₄,R′, R″ or any substituent on E of formula I can be of the formula Q-U—,for example,

wherein U is selected from the group consisting of oxygen, sulfur,nitrogen, OCH2, SCH2 and NHCH2; and Q is selected from the groupconsisting of hydrogen, alkyl, PEG-CO, HCO, acetyl, amino acid, boronicacid, substituted benzoic acid and phosphoric acid; or, wherein Q-U—together is selected from phosphonooxy, phosphonoalkyloxy, formyloxy,alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy,aminocarbonyloxyalkyloxy, alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, borono, boronoalkyl, carboxyalkyl, carboxyalkyloxy,alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy.

Similarly, in a compound of formula IIa any one of R₁, R₂, R₃, R₄, R₁₂,R₁₃, R₁₄, R₁₅, R₁₆, R′, or R″ could be of the formula Q-U— wherein U isselected from the group consisting of oxygen, sulfur, nitrogen, OCH₂,SCH₂ and NHCH₂; and Q is selected from the group consisting of hydrogen,alkyl, PEG-CO, HCO, acetyl, amino acid, boronic acid, substitutedbenzoic acid and phosphoric acid; or, wherein Q-U together is selectedfrom phosphonooxy, phosphonoalkyloxy, formyloxy, alkyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,alkylsulfinyloxy, alkylsulfonyloxy, carbamate, carbamido, borono,boronoalkyl, carboxyalkyl, carboxyalkyloxy, alkoxycarbonyl,alkylaminocarbonyl, aminocarbonyl, arylcarbonyloxy,arylalkylcarbonyloxy, aryloxycarbonyloxy, heterocyclylcarbonyloxy andheterocyclylalkylcarbonyloxy, each of which groups is substituted orunsubstituted.

Suitable prodrugs may include, but not be limited to, those illustratedbelow for a compound of formula IIa, specifically as novel prodrugderivatives of a typical compound:

wherein U is selected from the group consisting of oxygen, sulfur,nitrogen, OCH₂, SCH₂ and NHCH₂; and Q, for example, is selected from thegroup consisting of PEG-CO, HCO, acetyl, amino acid, boronic acid,substituted benzoic acid and phosphoric acid; or, Q-U together, forexample, is substituted or unsubstituted phosphonooxy,phosphonooxyalkyloxy, borono, boronoalkyl, carboxyalkyl,carboxyalkyloxy, alkyloxy, alkylcarbonyloxy, alkylcarbonyloxyalkyloxy,aminocarbonyloxy, aminocarbonyloxyalkyloxy, dimethylaminocarbonyloxy,dimethylaminocarbonyloxyalkyloxy, piperidinylcarbonyloxy,piperidinylcarbonyloxyalkyloxy, dipiperidinylcarbonyloxy, ordipiperidinylcarbonyloxyalkyloxy.

As used herein, the “alkyl” part of any of the substituents describedherein, e.g., including but not limited to, alkyl, alkylamino,alkylmercapto, hydroxyalkyl, polyhydroxyalkyl, alkylaminoalkyl,aminoalkyl, arylalkyl, arylcycloalkyl, heterocyclylalkyl, arylalkylenyl,arylcycloalkyl, dialkylamino, alkylcarbonyloxy, dialkylaminoalkyl,cyanoalkyl, haloalkyl, phosphonoalkyloxy, boronoalkyloxy,carboxyalkyloxy, alkylcarbonylalkylcarbonyloxy, dialkylalkylaminoalkyl,alkylsulfonyl, alkylsulfinyl, alkylsulfinyloxy, alkylsulfonyloxy,alkylenedioxy, carbocyclylalkyl, arylalkylcarbonyloxy,heteroarylcarbonyloxy, phenylalkyl, and the like, means a straight-chainor branched-chain saturated alkyl which can contain from 1-20 carbonatoms, for example from 1 to about 10 carbon atoms, or from 1 to about 8carbon atoms, or, preferably, lower alkyl, i.e., from 1 to 6 carbonatoms. Unless otherwise specified herein, “alkyl” is assumed to meanlower alkyl.

Examples of alkyls include methyl, ethyl, propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, pentyl, isoamyl, hexyl, octyl,dodecanyl, octadecyl, and the like. Alkyl substituents can beunsubstituted or substituted, for example with at least one substituentselected from the group consisting of a halogen, a nitro, an amino, ahydroxyl, a thio, an acyl, a mercapto, and a cyano.

The term “alkenyl” means a straight-chain or branched-chain alkenylhaving one or more double bonds. Unless otherwise specified, the alkenylcan contain from 2 to about 10 carbon atoms, for example from 2 to about8 carbon atoms, or preferably from 2 to about 6 carbon atoms. Examplesof alkenyls include vinyl, allyl, 1,4-butadienyl, and isopropenylsubstituents, and the like.

The term “alkynyl” means a straight-chain or branched-chain alkynylhaving one or more triple bonds. Unless otherwise specified, alkynylscan contain from 2 to about 10 carbon atoms, for example, from 2 toabout 8 carbon atoms, or preferably, from 2 to about 6 carbon atoms.Examples of alkynyls include ethynyl, propynyl (propargyl), butynyl, andthe like. Alkenyl or alkynyl substituents can be unsubstituted orsubstituted, for example, with at least one substituent selected fromthe group consisting of a halogen, a nitro, an amino, a hydroxyl, athio, an acyl, an alkyl, and a cyano.

The term “aryl” means an aromatic carbocyclic radical, as commonlyunderstood in the art, and includes monocyclic and polycyclic aromaticssuch as, for example, phenyl and naphthyl rings. Preferably, the arylcomprises one or more six-membered rings including, for example, phenyl,naphthyl, biphenyl, and the like. Typically, the aryl comprises six ormore carbon atoms in the ring skeleton thereof (e.g., from 6 to about 10carbon atoms making up the ring). Unless specified otherwise, “aryl” byitself refers to unsubstituted aryl groups and does not coversubstituted aryl groups. Substituted aryl can be an aryl substituted,for example, with at least one substituent selected from the groupconsisting of a halogen, a nitro, an amino, a hydroxyl, a thio, an acyl,and alkyl, and a cyano. It is to be noted that arylalkyl, benzyl, orheteroaryl groups are not considered “aryl” in accordance with thepresent invention.

In accordance with the invention, the term “heteroaryl” refers to acyclic aromatic radical having from five to ten ring atoms of which atleast one atom is O, S, or N, and the remaining atoms are carbon.Examples of heteroaryl radicals include pyridinyl, pyrazinyl,pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,and isoquinolinyl. Unless otherwise specified, “heteroaryl” refers tounsubstituted heteroaryl.

In further accordance with the invention, the term “heterocyclyl” refersto a stable, saturated, partially unsaturated or unsaturated monocyclic,bicyclic, or spiro ring system containing 3 to 7 ring members of carbonatoms and other atoms selected from nitrogen, sulfur, and/or oxygen. Theterm “heterocyclyl” includes “heteroaryl groups. Preferably, aheterocyclyl is a 5, 6, or 7-membered monocyclic ring and contains one,two, or three heteroatoms selected from nitrogen, oxygen, and/or sulfur.The heterocyclyl may be attached alone or via an alkyl linker (thusbecoming a “heterocyclylalkyl”) to the parent structure through a carbonatom or through any heteroatom of the heterocyclyl that results in astable structure. Examples of such heterocyclyl rings are isoxazolyl,thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl,pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl.

Further in accordance with the invention, unless otherwise specified,the term “heterocyclyl” refers to a saturated or unsaturated,unsubstituted ring consisting of 3-7 atoms, at least one of which is nota carbon atom, such as an oxygen, nitrogen or sulfur atom.

Whenever a range of the number of atoms in a structure is indicated(e.g., a C₁₋₁₂, C₁₋₈, C₁₋₆, or C₁₋₄ alkyl, alkylamino, etc.), it isspecifically contemplated that any sub-range or individual number ofcarbon atoms falling within the indicated range also can be used. Thus,for instance, the recitation of a range of 1-8 carbon atoms (e.g.,C₁-C₈), 1-6 carbon atoms (e.g., C₁-C₆), 1-4 carbon atoms (e.g., C₁-C₄),1-3 carbon atoms (e.g., C₁-C₃), or 2-8 carbon atoms (e.g., C₂-C₈) asused with respect to any chemical group (e.g., alkyl, alkylamino, etc.)referenced herein encompasses and specifically describes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well asany sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms,1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms,2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms,2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbonatoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbonatoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms,and/or 4-12 carbon atoms, etc., as appropriate).

Given the disclosures of the present invention, it will be appreciatedthat the compounds of the present invention can be made by methodswell-known to those of ordinary skill in the art, for example, bystructurally modifying a given compound or by direct synthesis fromavailable building blocks using routine synthetic transformations thatare well-known in the art. See for example, Sperl et al., U.S. PatentApplication Publication No. US 2003/0009033 A1, Jan. 9, 2003; Sperl etal., U.S. Pat. No. 6,071,934, Jun. 6, 2000; Sperl et al., InternationalPublication No. WO 97/47303, Dec. 18, 1997; Whitehead et al., U.S.Patent Application Publication No. US 2003/0176316 A1, Sep. 18, 2003;Thompson et al., U.S. Pat. No. 6,538,029 B1, Mar. 25, 2003; Li et al.,U.S. Patent Application Publication No. US 2003/0194750 A1, Oct. 16,2003; and Shen et al., U.S. Pat. No. 3,888,902, Jun. 10, 1975; Alcaldeet al., Org. Biomol. Chem., 6, 3795-3810 (2008); Magar and Lee, Org.Lett., 15, 4288-4291 (2013).

For instance, a compound of formula Ia or IIa can be synthesizedaccording to the general approach depicted in Scheme I:

Detailed methods to achieve all the synthesis steps depicted in Scheme Ito make a desired substituted or unsubstituted indene derivative, areextensively documented in the published literature (e.g., see Sperl etal., 1997, 2000, 2003, supra; Li, et. el., 2003, supra; Thompson et al.,2003, supra; Whitehead et al., 2003, supra); Alcatel et al., 2008,supra; Magar and Lee, 2013, supra; Shen et al., 1975, supra. In Scheme Ithe benzaldehyde building block used for step a, and/or the aldehydebuilding block (E-CHO) used for step f, and/or the primary or secondaryamine (R′R″NH) building block used in step g can independently beunsubstituted, or may be substituted with any desired substituent(s)required to yield the desired final product of the present invention.

For example, the benzaldehyde building block as shown in Scheme I withthe desired substituents at R₁, R₂, R₃ and R₄ can be purchasedcommercially and/or can be prepared routinely by methods well-known tothose of ordinary skill in the art. Such optional substituent(s)independently at R₁, R₂, R₃ and R₄ in Scheme I for example include butare not limited to hydrogen, halogen, alkyl, cycloalkyl, haloalkyl,hydroxyl, carboxyl, alkoxy, formyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto,alkylmercapto, cyano, cyanoalkyl, nitro, azido, and a substituted orunsubstituted group selected from alkylsulfinyloxy, alkylsulfonyloxy,carbamate, carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphono,phosphonothio, phosphonoamino, phosphonoalkyl, phosphonoalkylthio,phosphonoalkylamino, phosphonooxy, phosphonoalkyloxy, sulfonamido,polyethyleneglycoxy, polyethyleneglycoxyalkyl, thioureido, borono,boronoalkyl, boronoalkyloxy, aminosulfonyl, aminocarboxyl,aminocarbonylalkyloxy, aminocarbonylalkylthio, alkylcarbonylamino,aminoalkenylamino, alkylsulfonylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyalkyloxy, carboxyalkylamino, carboxyalkylthio,aminoalkyloxy, aminocarbonylthio, hydroxyalkyloxy, hydroxyalkylamino,hydroxyalkylthio, dialkylaminoalkyl, aminoalkylamino,alkylaminoalkylamino, dialkylaminoalkylamino, aminoalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, aminoalkylthio,alkylaminoalkylthio, dialkylaminoalkylthio and a saturated orunsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclicring comprising any two of R₁, R₂, R₃ and R₄;

Likewise, the aldehyde building block (E-CHO) as shown in Scheme I withany desired group at E can be purchased and/or can be prepared bymethods well-known to those of ordinary skill in the art. Such optionalgroups at E in Scheme I for example include but are not limited to anydesired substituted or unsubstituted, saturated or unsaturated,7-membered, 6-membered, 5-membered, 4-membered or 3-membered carbocyclicor heterocyclic ring. Substituents on said ring may include one or moreof hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, hydroxyl, carboxyl,alkoxy, formyloxy, hydroxyalkyl, aldehydo, amino, alkylamino,aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto, alkylmercapto,cyano, cyanoalkyl, nitro, azido, and a substituted or unsubstitutedgroup selected from alkylsulfinyloxy, alkylsulfonyloxy, carbamate,carbamido, alkoxycarbonyl, alkylaminocarbonyl, aminocarbonyl,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphono,phosphonothio, phosphonoamino, phosphonoalkyl, phosphonoalkylthio,phosphonoalkylamino, phosphonooxy, phosphonoalkyloxy, sulfonamido,polyethyleneglycoxy, polyethyleneglycoxyalkyl, thioureido, borono,boronoalkyl, boronoalkyloxy, aminosulfonyl, aminocarboxyl,aminocarbonylalkyloxy, aminocarbonylalkylthio, alkylcarbonylamino,aminoalkenylamino, alkylsulfonylamino, carboxyalkyl, carboxyalkenyl,carboxyalkynyl, carboxyalkyloxy, carboxyalkylamino, carboxyalkylthio,aminoalkyloxy, aminocarbonylthio, hydroxyalkyloxy, hydroxyalkylamino,hydroxyalkylthio, dialkylaminoalkyl, aminoalkylamino,alkylaminoalkylamino, dialkylaminoalkylamino, aminoalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, aminoalkylthio,alkylaminoalkylthio, dialkylaminoalkylthio and a saturated orunsaturated 3-, 4-, 5-, 6- or 7-membered carbocyclic or heterocyclicring comprising any two of R₁, R₂, R₃ and R₄;

Furthermore, the primary or secondary amine building block (R′R″NH) asshown in Scheme I can be purchased commercially and/or can be preparedroutinely by methods well-known to those of ordinary skill in the art.Such optional substituents independently at R′ and R″ in Scheme I forexample include but are not limited to hydrogen, hydroxyl, and asubstituted or unsubstituted group selected from alkyl, aryloxy,cyanoalkyl, haloalkyl, alkoxy, alkenyl, alkynyl, hydroxyalkyl,polyhydroxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminoalkyl,alkylamino, aryl, arylalkyl, arylalkenyl, arylcycloalkyl,arylcycloalkenyl, polyethyleneglycoxy, polyethyleneglycoxyalkyl,carbocyclyl, and carbocyclylalkyl where the carbocycle of thecarbocyclyl and the carbocyclylalkyl is selected from 7-memberedcarbocyclic rings containing no double bond, or one, two or three doublebonds, 6-membered carbocyclic rings containing no double bond, or one,two or three double bonds, 5-membered carbocyclic rings containing nodouble bond, or one or two double bonds, 4-membered carbocyclic ringscontaining no double bond or one double bond and 3-membered carbocyclicrings containing no double bond, heterocyclyl, and heterocyclylalkyl,where the heterocycle of the heterocyclyl and heterocyclylalkyl isselected from 7-membered heterocyclic rings, 6-membered heterocyclicrings, and 5-membered heterocyclic rings, and the aryl of the aryl,arylalkyl, arylalkylenyl, arylcycloalkyl, or arylcycloalkenyl structureor the carbocyclic or heterocyclic structure is optionally substitutedwith one or more of halo, alkyl, haloalkyl, hydroxyl, alkoxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido,aldehydo, cyano, oxo, alkylcarbonyloxy, sulfonamido and COR₁₁, whereinR₁₁ is selected from hydrogen, amino, alkyl, haloalkyl, alkoxy,alkylmercapto, and aryl; or R′ and R″ together form a 5-, 6- or7-membered, saturated or unsaturated, heterocyclic ring containing atleast one nitrogen and optionally oxygen or sulfur, and the heterocyclicring is optionally substituted with one or more of halo, alkyl,haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, mercapto,alkylmercapto, carboxamido, aldehydo, cyano, oxo, alkylcarbonyloxy, andsulfonamido.

As a more specific example, a desired precursor compound for making anew compound of formula IIa can be synthesized according to the generalapproach depicted in Scheme II, which includes the key intermediate, asubstituted indenyl acetic acid:

For certain substituents at R₁, R₂, R₃ or R₄ (e.g., in Scheme II above,R₂ is fluoro), the starting material for preparation of the substitutedindenyl acetic acid intermediate, is optionally different than thatshown in Schemes I and II, depending upon the nature of thesubstituent(s) desired on the intermediate and final product, and theoptimum reaction conditions sought. For example, attachment of a cyanogroup at R₂ can be accomplished using as starting material acyano-substituted benzyl halide (e.g., as adapted from Shen et al.,1975), as illustrated below in Scheme III:

A wide variety of substituents can be introduced at R₁, R₂, R₃ and R₄ ofa compound of formula Ia and IIa during synthesis. In addition to theabove-described Schemes I-III, Scheme IV below illustrates yet anotherapproach to making variations in substituents at R₁-R₄.

Extensive variations can also be made in R and/or R₀ in a medicallyuseful compound of formula Ia or IIa of the invention. For example, oneskilled in the art can use or adapt as necessary the general synthesisapproach illustrated by Scheme V below.

In a more specific example illustrated in Scheme VI below, an availablecompound of formula Ib can serve as the starting point for making new,medically useful derivatives thereof which have various substituents atR and/or R₀. This approach may likewise be adapted to make novelcompounds of the present invention by selection and incorporation ofappropriate building block compounds into the scheme.

Furthermore, variations in the length of the side-chain linkers in thecompounds of formula Ia and IIa can be introduced by one of ordinaryskill in the art by adapting known methods. For example, adaptations ofthe methods of Magar and Lee 2013, supra, can be used to produce suchcompounds wherein n=0.

One skilled in the art will also appreciate that Schemes I-IV can beused, with routine adaptations well-known to the skilled artisan, tomake compounds of formula Ia and IIa wherein R₅ and R₂₀ together form adouble bond, rather than wherein R₉ and R₂₀ together form a double bond.Such variations in location of the double bond within the cyclopentenepart of the indene core structure can be accomplished routinely byincorporating the appropriate precursors into the desired one or more ofScheme(s) I-VI above.

One skilled in the art will additionally know that Schemes I-VI can beused, with routine adaptations well-known to the skilled artisan, tomake compounds of the invention wherein neither R₅ and R₂₀ together, norR₉ and R₂₀ together, form a double bond. Such compounds, containing anindane core structure, rather than an indene core structure, can besynthesized routinely by using one or more of Scheme(s) I-VI andincorporating into the syntheses the appropriate precursor compound(s)which can also be made by the skilled artisan using well-establishedmethods in the art. Compounds of formula Ia and IIa wherein thepresence, absence or location of the double bond in the 5-membered ringcomponent of the core structure can also be made by appropriateadaptations of the Scheme(s) I-VI well-known to those of ordinary skillin the art.

The skill artisan will also appreciate that additional examples ofcompounds of formula Ia or IIa can be made using appropriate adaptationsof the well-established Scheme(s) I-VI, as well as other familiarapproaches illustrated in the following schemes.

Schemes VII-X illustrate various approached to synthesis of compounds offormula Ia and IIa wherein at least one of A₂, A₄, A₅, A₆ and A₇ is anitrogen atom, and Schemes XI and XII illustrate synthesis of compoundsof formula Ia or IIa wherein an amido side-chain is attached to A₁directly by a nitrogen-carbon bond, or where it is attached via an alkyllinker.

Placement, removal and/or inter-conversion of desired substituents onprecursors, building blocks, intermediates or penultimate productcompounds of formulas Ia and IIa can be accomplished by routine methodswell-known to those of ordinary skill in the art, such as for example,briefly overviewed in the following:

One or more hydroxyl groups, for example, can be converted to the oxoderivative by direct oxidation, which can be accomplished using anyknown method such as, for example, a Swern oxidation, or by reactionwith a metal oxidant, such as a chromium oxide (e.g., chromiumtrioxide), a manganese oxide (e.g., manganese dioxide or permanganate)or the like. Primary alcohols can be oxidized to aldehydes, for example,via Swern oxidation, or they can be oxidized to carboxylic acids (e.g.,—CO₂H), for example by reaction with a metal oxidant. Similarly, thethiols (e.g., —SR, —SH, and the like) can be converted to oxidizedsulfur derivatives (e.g., —SO₂R or the like) by reaction with anappropriate oxidant.

One or more hydroxyl groups can be converted to an ester (e.g., —CO₂R),for example, by reaction with an appropriate esterifying agent such asfor example, an anhydride (e.g., (R(CO))₂O) or an acid chloride (e.g.,R(CO)Cl), or the like. One or more hydroxyl groups can be converted to asulfonate (e.g., —SO₂R) by reaction with an appropriate sulfonatingagent such as, for example, a sulfonyl chloride (e.g., RSO₂Cl), or thelike, wherein R is any suitable substituent including, for example,organic substituents described herein. Ester derivatives also can beobtained, for example, by reacting one or more carboxylic acidsubstituents (e.g., —CO₂H) with an alkylating agent such as, forexample, a diazoalkane (e.g., diazomethane) an alkyl or aryl iodide, orthe like. One or more amides can be obtained by reaction of one or morecarboxylic acids with an amine under appropriate amide-formingconditions which include, for example, activation of a carboxylic acid(e.g., by conversion to an acid chloride or by reaction with acarbodiimide reagent) followed by coupling of the activated species witha suitable amine.

One or more hydroxyl groups can be converted to a halogen using ahalogenating agent such as, for example, an N-halosuccinamide such asN-iodosuccinamide, N-bromosuccinamide, N-chlorosuccinamide, or the like,in the presence of a suitable activating agent (e.g., a phosphine, orthe like). One or more hydroxyl groups also can be converted to ether byreacting one or more hydroxyls, for example, with an alkylating agent inthe presence of a suitable base. Suitable alkylating agents can include,for example, an alkyl or aryl sulfonate, an alkyl or aryl halide, or thelike. One or more suitably activated hydroxyls, for example a sulfonateester, and/or one or more suitably activated halides, can be convertedto the corresponding cyano, halo, or amino derivative by displacementwith a nucleophile which can include, for example, a thiol, a cyano, ahalide ion, or an amine (e.g., H₂NR, wherein R is a desiredsubstituent), or the like.

Amines can be obtained by a variety of methods known in the art, forexample, by hydrolysis of one or more amide groups. Amines also can beobtained by reacting one or more suitable oxo groups (e.g., an aldehydeor ketone) with one or more suitable amines under the appropriateconditions, for example, reductive amination conditions, or the like.One or more amines, in turn, can be converted to a number of otheruseful derivatives such as, for example, amides, sulfonamides, and thelike.

Certain chemical modifications of a compound of formula Ia and IIa canbe introduced as desired to obtain useful new variants with new ormodified biological properties such as: new or improved potency and/orselectivity for inhibiting Ras-mediated biological processes, improvedefficacy against a disease process such as, but not limited to, tumorcell growth, proliferation, survival, invasion and metastasis, as wellas resistance to chemotherapy, other molecularly targeted therapeutics,and radiation, as well as enhanced oral bioavailability, less toxicityin a particular host mammal, more advantageous pharmacokinetics and/ortissue distribution in a given host mammal, and the like. Therefore, thepresent invention employs methods for obtaining useful new compounds offormula Ia and IIa by applying one or more well-known chemical reactionsto a given compound to obtain a derivative wherein, for example, one ormore phenolic hydroxyl group(s) may instead be replaced by an ester,sulfonate ester or ether group; one or more methyl ether group(s) mayinstead be replaced by a phenolic hydroxyl group; one or more phenolichydroxyl group(s) may instead be replaced by an aromatic hydrocarbonsubstituent; a secondary amine site may instead be replaced by an amide,sulfonamide, tertiary amine, or alkyl quaternary ammonium salt; atertiary amine site may instead be replaced by a secondary amine; andone or more aromatic hydrogen substituent(s) may instead be replaced bya halogen, nitro, amino, hydroxyl, thiol or cyano substituent.

Depending upon the stoichiometric amount of the selected reactant, acompound of formula Ia or IIa can be substituted at one, some, or all ofthe respective available positions. For example, when such a compound isreacted with a certain amount of CH₃COCl, an acetate substituent can beintroduced a one, some, or all of the available positions, which mayinclude, for example ether or amino positions.

Other examples may include, but are not limited to: (1) conversion toester, sulfonate ester, and ether substituents at one or more phenolichydroxyl positions in compounds of formula Ia and IIa; for instance, forpreparation of esters or sulfonate esters a given compound can bereacted with an acid halide (e.g., RCOX or RSO₂X, where X is Cl, Br orI, and R is a C₁-C₆ aliphatic or aromatic radical) in anhydrous pyridineor triethylamine; alternatively, the given compound may be reacted withan acid (RCO₂H or RSO₃H) wherein R is an aliphatic or aromatic radicaland dicyclohexylcarbodiimide in triethylamine to prepare the ester orsulfonate ester; for preparation of ethers, the given compound isreacted with an organic halide (e.g., RX or RCH₂X, where X is Cl, Br orI, and R is a C₁-C₆ aliphatic or aromatic radical) in anhydrous acetonewith anhydrous potassium carbonate; (2) removal of an ether methylgroup(s) to provide a phenolic hydroxyl functionality and/or conversionof that moiety to an ester, sulfonate, or other ether in a compound orderivative of formula Ia and IIa: for instance, for hydrolytic cleavageof a methyl ether substituent and conversion to a phenolic hydroxylmoiety, the given compound is reacted with BBr₃ or BX₃.(CH₃)₂S in CH₂Cl₂(where X is F, Cl or Br); the resulting phenol can be converted to anester, sulfonate ester or ether as described above; (3) preparation ofamide or sulfonamide derivatives at an amine site in a compound offormula Ia or IIa: for instance, for preparation of amides orsulfonamide derivatives, the same general procedures described above in(1) apply; in either case (procedure (1) or (3)), an appropriatefunctional group protection strategy (blocking/deblocking of selectedgroup(s)) may need to be applied; (4) conversion of a secondary aminefunctionality in a compound of formula Ia or IIa to a tertiary amine:for instance, for preparation of a tertiary amine, the given compound isreacted with an aldehyde, and the resulting product is then reduced withNaBH₄; alternatively, for preparation of an alkyl ammonium salt, thegiven compound is reacted with an alkyl halide (RX, where X is Cl, Br orI, and R is a C₁-C₆ aliphatic radical) in an anhydrous aprotic solvent;(5) conversion of a tertiary amine functionality in a compound offormula Ia or IIa to a secondary amine; for instance, for preparation ofa secondary amine, the given compound is reacted with cyanogen bromideto give a cyanamide derivative which is then treated with LiAlH₄; (6)conversion of one or more phenolic hydroxyl groups in a given compoundof formula Ia or IIa to an aromatic hydrogen substituent: for instance,the given compound is converted (after suitable protection of any aminesubstituent(s) if necessary) to the triflate ester to give thecorresponding deoxy compound; (7) substitution of one or more hydrogensubstituent(s) on the aryl system(s) on a compound of formula Ia or IIaby halogen, nitro, amino, hydroxyl, thiol, or cyano groups: forinstance, for preparation of a bromine-substituted derivative, the givencompound is reacted with Br₂ in H₂O; for the preparation of othersubstituted derivatives, the given compound is treated with HNO₃/HOAc toprovide a nitro-substituted (—NO₂) derivative; in turn, thenitro-derivative can be reduced to an amino derivative, and the aminoderivative is the point of origin of the chloro, iodo, cyano, thiol andhydroxyl substitution via well-known and practiced diazoniumsubstitution reactions. More detailed, specific illustrations ofsynthesis and derivatization procedures that can be employed to accessany desired member of the family of compounds represented by formulas Iaand IIa and derivatives thereof, are provided in the examples thatfollow herein.

It will be appreciated that certain compounds of formula Ia and, IIa canhave one or more asymmetric carbon(s) and thus such compounds arecapable of existing as enantiomers or diastereomers. Unless otherwisespecified, the present invention includes such enantiomers ordiastereomers, including any racemates thereof. If desired, the separateenantiomers or diastereomers can be synthesized from appropriate chiralstarting materials, or the racemates can be resolved by conventionalprocedures, which are well-known to those skilled in the art, such aschiral chromatography, fractional crystallization of diastereomers ordiastereomeric salts, and the like. Certain compounds can exist asgeometrical isomers, such as, for example, compounds with double-bondedsubstituents with geometrical isomers Z and E, and the present inventionincludes all such isomers, including certain isomers, for example the Zisomers, which are preferred. Also, certain compounds may containsubstituents wherein there is restricted rotation and/or other geometricisomers are possible. For example, certain oxime substituents may existin syn or anti configurations. The present invention includes all suchconfigurations, including all possible hindered-rotational isomers, andother geometric isomers. The present invention also includes allpositional isomers wherein a given substituent, for example aheterocyclic substituent such as furanyl or pyrazolyl, may be connectedto the core molecule via different atoms of the heterocyclic ring (e.g.,2-furanyl, 3-furanyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, and thelike).

It will be appreciated by one skilled in the art that the proof orconfirmation of the chemical structure of a compound provided by or usedin the present invention can be demonstrated using at least one or morewell-known and established, convergent methods including, but notlimited to, for example: proton and/or carbon NMR spectroscopy, massspectrometry, x-ray crystallography, chemical degradation, and the like.

One or more compound(s) of formula Ia or IIa or pharmaceuticallyacceptable salt(s) or prodrugs(s) thereof can be included in acomposition, e.g., a pharmaceutical composition. In that respect, thepresent invention further provides a composition that includes aneffective amount of at least one compound of formula Ia or IIa which maybe in the form of pharmaceutically acceptable salt(s) or prodrug(s)thereof and a pharmaceutically acceptable carrier. The composition ofthe present invention preferably includes a therapeutically orprophylactically effective amount of at least one compound of formula Iaor IIa. The therapeutically or prophylactically effective amount caninclude an amount that produces a therapeutic or prophylactic responsein a patient to whom a compound or composition of the present inventionis administered. A therapeutically or prophylactically effective amountcan include, for example, a Ras-inhibitory and/or an anticancereffective amount.

The composition of the present invention can further include atherapeutically or prophylactically effective amount of at least oneadditional compound other than a compound of formula Ia or IIa, whichmay or may not be a Ras-inhibitory compound, which may be an anticancercompound. When the additional compound is a Ras-inhibitory compoundother than a compound of formula Ia or IIa, it is preferably present inthe composition in a Ras-inhibiting amount. When the additional compoundis an anticancer compound in general, it is preferably present in thecomposition in an anticancer effective amount.

The composition of the present invention can be produced by combiningone or more compound(s) of formula Ia or IIa with an appropriatepharmaceutically acceptable carrier, and can be formulated into asuitable preparation, which may include, for example, preparations insolid, semi-solid, liquid or gaseous forms such as tablets, capsules,powers, granules, ointments, solutions, suppositories, injections,inhalants, and aerosols, and other formulations known in the art fortheir respective routes of administration. In pharmaceutical dosageforms, a compound of formula Ia or IIa can be used alone or inappropriate association, as well as in combination, with otherpharmacologically active compounds, including other compounds, e.g.,other Ras-inhibitory compounds, as described herein.

Any suitable pharmacologically or physiologically acceptable carrier canbe utilized. The following methods and carriers are merely exemplary andare in no way limiting. In the case of oral preparations, a compound offormula Ia or IIa can be administered alone or in combination with atherapeutically or prophylactically effective amount of at least oneother compound. The active ingredient(s) can be combined, if desired,with appropriate additives to make tablets, powders, granules, capsulesor the like.

Suitable additives can include, for example, lactose, mannitol, cornstarch or potato starch. Suitable additives also can include binders,for example crystalline cellulose, cellulose derivatives, acacia, orgelatins; disintegrants, for example, corn starch, potato starch orsodium carboxymethylcellulose; or lubricants such as talc or magnesiumstearate. If desired, other additives such as, for example, diluents,buffering agents, moistening agents, preservatives, and/or flavoringagents, and the like, can be included in the composition.

The compounds used in accordance with the present invention can beformulated into a preparation for injection or infusion by dissolution,suspension, or emulsification in an aqueous or non-aqueous solvent, suchas vegetable oil, synthetic aliphatic acid glycerides, esters of higheraliphatic acid or propylene glycol (if desired, with conventionaladditives such as solubilizers isotonic agents, suspending agents,emulsifying agents, stabilizers, and preservatives).

The compounds of formula Ia and IIa also can be made into an aerosolformulation to be administered by inhalation. Such aerosol formulationscan be placed into pressurized acceptable propellants such asdichlorodifluoromethane, propane, nitrogen, and the like.

The compounds of the invention can be formulated into suppositories byadmixture with a variety of bases such as emulsifying bases orwater-soluble bases. The suppository formulations can be administeredrectally, and can include vehicles such as cocoa butter, carbowaxes, andpolyethylene glycols, which melt at body temperature but are solid atroom temperature.

Unit dosage forms for oral or rectal administration such as syrups,elixirs, and suspensions can be provided wherein each dosage unit, e.g.,teaspoonful, tablet, or suppository contains a predetermined amount ofthe composition containing the compound of formula Ia or IIa. Similarly,unit dosage forms for injection or intravenous administration cancomprise a composition as a solution in sterile water, normal saline, orother pharmaceutically acceptable carrier.

The term “unit dosage form” as used herein refers to physically discreteunits suitable as unitary dosages for human and animal subjects, eachunit containing a predetermined quantity of at least one compound(s) offormula Ia or IIa (alone, or if desired, with another therapeutic orprophylactic agent). The unit dosage can be determined by methods knownto those of skill in the art, for example, by calculating the amount ofactive ingredient sufficient to produce the desired effect inassociation with a pharmaceutically acceptable carrier. Thespecifications for the unit dosage forms that can be used in accordancewith the present invention depend on the desired effect to be achievedand the pharmacodynamics associated with the compound(s) in theindividual host.

Pharmaceutically acceptable carriers, for example, vehicles, adjuvants,excipients, or diluents, are accessible to those of skill in the art andare typically available commercially. One skilled in the art can easilydetermine the appropriate method of administration for the exactformulation of the composition being used. Any necessary adjustments indose can readily be made by an ordinarily skilled practitioner toaddress the nature or severity of the condition being treated.Adjustments in dose also can be made based on other factors such as, forexample, the individual patient's overall physical health, sex age,prior medical history, and the like.

The compounds of formula Ia and IIa can be utilized in a variety oftherapeutic and prophylactic (disease preventing) applications, and alsoin certain non-therapeutic or non-prophylactic applications. It will beappreciated that one or more of these compounds can be used, forexample, as a control in diagnostic kits, bioassays, or the like.Preferably the method of the present invention is appliedtherapeutically or prophylactically, for example, toward treatment orprevention of cancer or toward treatment or prevention of a condition(e.g. an abnormal condition or disease) treatable by the inhibition ofRas-mediated biological process(es). The compounds of formula Ia and IIacan be administered alone, or in combination with a therapeutically orprophylactically effective amount of at least one additional compoundother than a compound of formula Ia or IIa.

Accordingly, the present invention further provides a method oftherapeutically or prophylactically treating a condition treatable byinhibition of one or more Ras-mediated biological processes, whichmethod includes administering to a patient a Ras-inhibiting amount of atleast one Ras-inhibitory compound of formula Ia or IIa. Moreparticularly, the present invention provides a method of therapeuticallyor prophylactically treating a condition treatable by the inhibition ofone or more Ras-mediated biological processes, which includesadministering a Ras-inhibiting effective amount of at least one compoundof formula Ia or IIa.

Many different abnormal conditions and diseases can be treated inaccordance with the method of the present invention. The compounds offormulas Ia and IIa, and their compositions can be used medically toregulate biological phenomena, including but not limited to suchRas-modulated processes as tumor cell growth, proliferation, survival,invasion and metastasis, as well as resistance to chemotherapy, othermolecularly targeted therapeutics, and radiation. The compounds offormula Ia and IIa are therefore useful in the treatment of diseases andconditions that can be controlled by the inhibition of Ras-mediatedcellular functions. Such diseases include, for example, diseases whereinhyperactive Ras (e.g., including mutant Ras) is implicated; suchdiseases prominently include cancer, among others. Compounds of formulaIa and IIa can be expected to have efficacious actions in patients withcancer, especially in patients whose cancers have underlyinghyperactive, over-expressed or mutant Ras-mediated pathologicalprocesses that are inhibited by a compound(s) of formula Ia or IIa.Hyperactive Ras may not only result from an activating mutation in theras gene, but alternatively may result from an activating mutation in oroverexpression of an upstream factor, such as a growth factor, thatactivates Ras. Compounds of the invention are expected to inhibitactivated Ras and Ras-mediated disease conditions regardless of themechanism by which the Ras is hyperactivated. Other aberrantRas-mediated diseases or conditions that are expected to be treatable orpreventable by administration of Ras-inhibiting amounts of compound(s)of the invention include for example, neurofibromatosis and Costellosyndrome. In the instance of cancer particularly, compound(s) of formulaIa and IIa may promote broader sensitivity of cancer to other drugsand/or radiation therapy by inhibiting the ability of cancer cells todevelop or express resistance to such drugs and/or radiation therapymaking possible the effective chemotherapeutic and/or radiotherapeutictreatment of cancer.

In accordance with an embodiment of the method of the presentintervention, it is preferred that a Ras-inhibiting effective amount isused. In that regard, it is preferred that the Ras-inhibiting amount iseffective to inhibit one or more conditions selected from the groupconsisting of tumor cell growth, proliferation, survival, invasion andmetastasis, as well as resistance to chemotherapy, other molecularlytargeted therapeutics, and radiation.

The method of the present invention further includes administering aRas-inhibiting effective amount of at least one additional compoundother than a compound of formula Ia or IIa. In some instances, themethod of the present invention can be made more effective byadministering one or more other Ras-inhibitory compound(s), along with acompound of formula Ia or IIa. One or more Ras-inhibitory compound(s) offormula Ia or IIa also can be co-administered in combination with ananticancer agent other than a compound of formula Ia or IIa, forexample, to cause anticancer chemotherapy-resistant and/orradiation-resistant tumor cells to become chemotherapy-sensitive and/orradiation-sensitive and/or to inhibit de novo the development of cancercell resistance to the anticancer agent and/or to cancer cell resistanceto radiation treatment.

In accordance with an embodiment of the method, the patient ispre-selected by utilizing an assay of said patient's tissue, blood ortumor for an abnormal, mutant or hyperactive ras gene or Ras protein, oran aberrant Ras-mediated biological process.

In accordance with the methods of the present invention, one or morecompounds of formula Ia or IIa can be administered by any suitable routeincluding, for example, oral or parenteral, including intravenous,subcutaneous, intraarterial, intraperitoneal, ophthalmic, intramuscular,buccal, rectal, vaginal, intraorbital, intracerebral, intracranial,intraspinal, intraventricular, intrathecal, intracisternal,intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, orvia inhalation. For example, one or more compound(s) of formula Ia orIIa can be administered as a solution that is suitable for intravenousinjection or infusion, or can be administered as a tablet, a capsule, orthe like, in any other suitable composition or formulation as describedherein. Accordingly, there is a wide variety of suitable formulations ofthe pharmaceutical composition of the present invention. Theformulations may also be applied topically.

The “Ras-inhibiting-effective amount” as utilized in accordance with anembodiment of the composition and method of the present invention,includes the dose necessary to achieve a “Ras-inhibiting effectivelevel” of the active compound in an individual patient. TheRas-inhibiting-effective amount can be defined, for example, as thatamount required to be administered to an individual patient to achievein said patient a Ras-inhibiting-effective blood or tissue level, and/orintracellular target-inhibiting level of a compound of formula Ia or IIato cause the desired medical treatment.

By way of example and not intending to limit the invention, the dose ofthe pharmaceutically active agent(s) described herein for methods ofpreventing or treating a disease or disorder can be, in embodiments,about 0.001 to about 1 mg/kg body weight of the subject being treatedper day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg,0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day. In certainembodiments, the dose of the pharmaceutically active agent(s) describedherein can be about 1 to about 1000 mg/kg body weight of the subjectbeing treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500mg, 750 mg, or 1000 mg/kg body weight per day.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, theinventive methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10%. Furthermore, the treatment, prevention, amelioration, orinhibition provided by the inventive method can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder, e.g., cancer. Also, for purposes herein,“treatment,” “prevention,” “amelioration,” or “inhibition” can encompassdelaying the onset of the disorder, or a symptom or condition thereof.

When the effective level is used as the preferred endpoint for dosing,the actual dose and schedule can vary depending, for example, uponinter-individual differences in pharmacokinetics, drug distribution,metabolism, and the like. The effective level also can vary when one ormore compound(s) of formula Ia or IIa are used in combination with othertherapeutic agents, for example, one or more additional anticancercompound(s), or a combination thereof. Moreover, the effective level canvary depending upon the selected disease (e.g., cancer orneurofibromatosis) or biological process (e.g., tumor cell growth,proliferation, survival, invasion and metastasis, as well as resistanceto chemotherapy, other molecularly targeted therapeutics, and radiation)for which treatment is desired. Similarly, the effective level can varydepending on whether the treatment is for therapy or prevention of aselected disease such as, for example, cancer.

Compounds of formula Ia and IIa can be expected to be broadlyefficacious anticancer agents, which will inhibit or destroy human solidtumors, and as well non-solid cancer such as leukemias and certainlymphomas. Solid tumors may include particularly those tumors where rasgene mutations are highly prevalent, such as pancreatic cancer, lungcancer and colon cancer, as well as diverse other solid tumors such as,for example, melanoma, ovarian cancer, renal cancer, prostate cancer,head and neck cancer, endocrine tumors, uterine cancer, breast cancer,sarcomas, gastric cancer, hepatic cancer, esophageal cancer, centralnervous system (e.g., brain) cancer, hepatic cancer, germline cancer,and the like.

In a preferred embodiment of the present invention, patients who aremost likely to have a favorable response to a Ras-inhibitory compound offormula Ia or IIa can be pre-selected, prior to said treatment with saidcompound, by assaying said patient's blood, tissues or tumor for thepresence ras gene mutations and/or abnormal Ras proteins and/or aberrantRas-mediated biological function(s), using assay procedures (includinguse of commercially available assay kits) well-known to those ofordinary skill in the art.

Accordingly, the present invention further provides a method oftherapeutically or prophylactically treating cancer, which methodcomprises administering to a patient in need thereof an anticancereffective amount of at least one Ras-inhibitory compound(s) of formulaIa or IIa. The anticancer effective amount can be determined, forexample, by determining an amount to be administered effective toproduce a Ras-inhibiting-effective blood or tissue level and/orintracellular target-inhibiting “effective level” in the subjectpatient. The effective level can be chosen, for example, as that bloodand/or tissue level (e.g., 10¹²-10⁻⁶ M from examples that follow)effective to inhibit the proliferation of tumor cells in a screeningassay. Similarly, the effective level can be determined, for example,based on the blood, tissue or tumor level in a patient that correspondsto a concentration of a therapeutic agent that effectively inhibits thegrowth of a human cancer in any assay that is clinically predictive ofanticancer activity. Further, the effective level can be determined, forexample based on a concentration at which certain markers of cancer in apatient's blood or tumor tissue (e.g., mutant or hyperactive ras gene(s)and/or Ras protein(s) and/or aberrant Ras-mediated biologicalpathway(s)) are inhibited by a selected compound that inhibits cancer.Alternatively, the effective level can be determined, for example, basedon a concentration effective to slow or stop the growth of a patient'scancer, or cause a patient's cancer to regress or disappear, or render apatient asymptomatic to a selected cancer, or improve a cancer patient'ssubjective sense of condition. The anticancer effective level can thenbe used to approximate (e.g., by extrapolation) or even to determineprecisely, the level which is required clinically to achieve aRas-inhibiting-effective blood, tissue, tumor and/or intracellular levelto cause the desired medical treatment. It will be appreciated that thedetermination of the therapeutically effective amount clinicallyrequired to effectively inhibit Ras-mediated processes also requiresconsideration of other variables that can influence the effective level,as discussed herein. When a fixed effective amount is used as apreferred endpoint for dosing, the actual dose and dosing schedule fordrug administration can vary for each patient depending upon factorsthat include, for example, inter-individual differences inpharmacokinetics, drug absorption, drug disposition and tissuedistribution, drug metabolism, drug excretion, whether other drugs areused in combination, or other factors described herein that influencethe effective level.

One skilled in the art and knowing and understanding the disclosures ofthe present invention can readily determine the appropriate dose,schedule, or method of administering a selected formulation, in order toachieve the desired effective level in an individual patient. Given thedisclosures herein, one skilled in the art also can readily determineand use an appropriate indicator of the effective level of thecompound(s) of formula Ia and IIa. For example, the effective level canbe determined by direct analysis (e.g., analytical chemistry) or byindirect analysis (e.g., with clinical chemistry indicators) ofappropriate patient samples (e.g., blood and/or tissues). The effectivelevel also can be determined, for example, if the compound in questionhas antitumor activity, by direct or indirect observations, such as, forexample, observing the shrinkage, slowing or cessation of growth orspreading of a tumor in a cancer patient. There are many references tothe art that describe the protocols used in administering and monitoringresponses to active compounds in a patient in need thereof. For example,drug-appropriate protocols used in the administration of different typesof anticancer agents to patients are described in “Cancer Chemotherapyand Biotherapy: Principles and Practice” eds. Chabner and Longo,Lippincott, Williams and Wilkins (2011), and citations therein.

The present inventive method of therapeutically or prophylacticallytreating cancer further includes administering an anticancer effectiveamount of at least one additional compound other than a compound offormula Ia or IIa. For example, one or more compound(s) of formula Ia orIIa can be co-administered with an anticancer agent, and/or can beco-administered with radiation therapy, in which case the effectivelevel is the level needed to inhibit or reverse the ability of thecancer to develop resistance to the anticancer agent and/or to theradiation therapy, respectively.

Examples of anticancer compounds include reversible DNA binders, DNAalkylators, and DNA strand breakers. Examples of suitable reversible DNAbinders include topetecan hydrochloride, irinotecan (CPT11—Camptosar),rubitecan, exatecan, nalidixic acid, TAS-103, etoposide, acridines(e.g., amsacrine, aminocrine), actinomycins (e.g., actinomycin D),anthracyclines (e.g., doxorubicin, daunorubicin), benzophenainse, XR11576/MLN 576, benzopyridoindoles, Mitoxantrone, AQ4, Etopside,Teniposide, (epipodophyllotoxins), and bisintercalating agents such astriostin A and echinomycin.

Examples of suitable DNA alkylators include sulfur mustard, the nitrogenmustards (e.g., mechlorethamine), chlorambucil, melphalan,ethyleneimines (e.g., triethylenemelamine, carboquone, diaziquone),methyl methanesulfonate, busulfan, CC-1065, duocarmycins (e.g.,duocarmycin A, duocarmycin SA), metabolically activated alkylatingagents such as nitrosoureas (e.g., carmustine, lomustine,(2-chloroethyl)nitrosoureas), triazine antitumor drugs such astriazenoimidazole (e.g., dacarbazine), mitomycin C, leinamycin, and thelike.

Examples of suitable DNA strand breakers include doxorubicin anddaunorubicin (which are also reversible DNA binders), otheranthracyclines, belomycins, tirapazamine, enediyne antitumor antibioticssuch as neocarzinostatin, esperamicins, calicheamicins, dynemicin A,hedarcidin, C-1027, N1999A2, esperamicins, zinostatin, and the like.

Examples of anticancer agents include abarelix, aldesleukin,alemtuzumab, altretamine, amifostine, aminoglutethimide, anastrazole,arsenic trioxide, asparaginase, azacitidine, azathioprine, BCG vaccine,bevacizumab, bexarotene, bicalutamide, bleomycin sulfate, bortezomib,bromocriptine, busulfan, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, chloroquine phosphate, cladribine,cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin,daunorubicin hydrochloride, daunorubicin citrate liposomal, dexrazoxane,docetaxel, doxorubicin hydrochloride, doxorubicin hydrochlorideliposomal, epirubicin hydrochloride, estramustine phosphate sodium,etoposide, estretinate, exemestane, floxuridine, fludarabine phosphate,fluorouracil, fluoxymesterone, flutamide, fulvestrant, gefitinib,gemcitabine hydrochloride, gemtuzumab ozogamicin, goserelin acetate,hydroxyurea, idarubicin hydrochloride, ifosfamide, imtinib mesylate,interferon alfa-2a, interferon alfa-2b, irinotecan hydrochloridetrihydrate, letrozole, leucovorin calcium, leuprolide acetate,levamisole hydrochloride, lomustine, lymphocyte immune anti-thymocyteglobulin (equine), mechlorethamine hydrochloride, medoxyprogestoneacetate, melphalan, mercaptopurine, mesna, methotrexate, mitomycin,mitotane, mitoxantrone hydrochloride, nilutamide, oxaliplatin,paclitaxel, pegaspargase, pentostatin, plicamycin, porfimer sodium,procarbazine hydrochloride, streptozocin, tamoxifen citrate,temozolomide, teniposide, testolactone, testosterone propionate,thioguaine, thiotepa, topotecan hydrochloride, tretinoin, uracilmustard, valrubicin, vinblastine sulfate, vincristine sulfate, andvinorelbine.

Suitable forms of radiation therapy include, for example, all forms ofradiation therapy approved for commercial use in the United States, andthose forms that will become approved in the future, for which radiationresistance thereto can be controlled by a Ras-inhibitory compound offormula Ia or IIa.

In accordance with an embodiment of the methods of the presentinvention, prophylaxis includes inhibition as described herein, e.g.,inhibition of the growth or proliferation of cancer cells, or inhibitionof aberrant Ras-mediated cellular functions. The inhibition can be lessthan 100% inhibition to be prophylactically effective, and a clinicallydesirable therapeutic benefit can be realized with less than 100%inhibition.

The compound(s) of formula Ia or IIa used in accordance with the presentinvention can be selected, for example, based upon the potency and/orselectivity for inhibiting Ras-mediated cellular processes, as assessedby in vitro or in vivo assays, and/or based on other pharmacological,toxicological, pharmaceutical or other pertinent considerations that arewell-known to those skilled in the art. Routine methods for the specificbioassay, quantitation and comparisons of Ras-inhibitory inhibitory andother biological activities and properties of compounds of formula Iaand IIa in various tissues, cells, organelles and other preparations, aswell as in vivo testing in animals are well-documented in the literature(e.g., see Teicher and Andrews (eds.), Anticancer Drug DevelopmentGuide, Humana (2004), and various authors and chapters therein). Morespecific illustrations of these and other details pertinent toenablement of the present invention are provided in the examples whichfollow.

The following examples further illustrate the invention but, of course,should not be construed as in any way limiting its scope.

Example 1

One skilled in the art and knowing the disclosures of the presentinvention will appreciate that any of compounds of formula Ia and IIacan be made or modified with different substituents as desired to be inthe final products, and/or the final product of a synthesis, for examplea synthesis according to any one or more of Schemes I, II, III, IV, V,VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI can be modifiedwith different substituents as desired.

Other modifications of molecules of formula Ia and IIa may be desirable,for example to remove extended conjugation to eliminate the potentialfor toxicity in certain situations, while retaining the desiredRas-inhibitory activity. For example, certain compounds of formula IIawherein R₅ and R₆ together form a carbon-carbon bond and R₉ and R₂₀together form a carbon-carbon bond and which have a phenolic hydroxylgroup at R₁₄ are among the most highly potent and selective Rasinhibitors of the invention. De-protonation of the phenolic hydroxyl insuch a structure either ex vivo or in vivo may lead to the formation ofa quinoid-like configuration comprising an oxo at R₁₄ which then createsan extended conjugation with the double bonds formed when R₅-R₆ togetheris a carbon-carbon bond and R₉-R₂₀ together is a carbon-carbon bond. Incertain situations, it may be desirable to eliminate the possibility ofsuch extended conjugation by not having one or both double bond(s) thatexist when R₅ and R₆ together is a carbon-carbon bond and/or when R₉ andR₂₀ together is a carbon-carbon bond, and/or by having an alternative tothe phenolic hydroxyl group, e.g., a bioisosteric equivalent or acleavable alcohol promoiety or a group that is converted within or nearthe target tumor cells to a phenolic hydroxyl group or a bioisostericequivalent. For making such partially reduced compounds, one skilled inthe art can modify (e.g., catalytic hydrogenation of double bond(s))existing compounds or precursors of formula Ia or IIa, and/or make useof appropriate available reduced or partially reduced, commercially orroutinely available precursors for use as building blocks to synthesizethe desired final compound structures, for example through use of one ormore of the schemes I-XVI, or modifications or adaptations thereof orother approaches well-known to those skilled in the art. A typicalhydrogenation is illustrated as follows:

The illustrative scheme shows preparation of an exemplary compound,1782. In a typical small-scale procedure, to a solution of the precursorcompound ADT-011 (100 mg) in EtOH (10 mL), Pd/C (5%, 10 mg) is added andthe suspension is stirred in an atmosphere of hydrogen at roomtemperature for 4 h. The catalyst is removed by filtration and thefiltrate is concentrated. The residue is purified by silica gel columnto afford 1781 as a colorless solid, typically in about 80% yield; then,to a solution of 1781 (100 mg) in EtOH (10 mL), Pd/C (5%, 20 mg) isadded and the suspension is stirred in an atmosphere of hydrogen at roomtemperature overnight; the catalyst is removed by filtration and thefiltrate is concentrated; the residue is purified by silica gel columnto afford the 1782 as a colorless solid, typically in about 80% yield.Using a similar procedure, many different related compounds of theinvention, such as for example the Ras inhibitors 1765 and 1796, can bereadily prepared by one skilled in the art.

In certain situations, a compound of formula Ia or IIa may require foroptimal target interaction (e.g., interaction with Ras) the molecularrigidity imposed by the double bond that exists when R₅ and R₆ togetherform a carbon-carbon bond. Therefore, in certain situations when R₅ andR₆ do not together form a carbon-carbon bond, it may be desirable tohave substituents or connectivity at R₅ and R₆ in other ways to imposesome molecular rigidity (e.g., hindered rotation about the existingcarbon-carbon bond between the carbons to which the R₅ and R₆ areattached). This can be realized, for example, by imposing features suchas the following in a compound of formula Ia or IIa: at least one, orpreferably two or three of R₅, R₆ and R₇ are large bulky groups, such ashalo (e.g., fluoro), t-butyl, and the like; or, R₅ and R₆ together withthe atoms to which they are attached form a ring, or R₆ and R₇ togetherwith the atom to which they are attached form a ring. Some examples ofapproaches that one skilled in the art may use to make such compoundsare exemplified as follows;

In another example, it may be desirable to have a rigid cyclic structurebetween the indenyl core and the attached phenyl group, such as in acompound of formula Ia or IIa when R₅ and R₆ together with the atoms towhich they are attached form a ring; alternatively, or additionally, itmay be desirable to have a bulky halo group located near the rigidcyclic structure. Such a compound of formula Ia or IIa can be preparedby one skilled in the art by a procedure such as exemplified in thefollowing:

Another way to impose desired molecular rigidity with preservation ofthe desired biological activity in a compound of formula Ia or IIa is byhaving a double bond within the indene ring wherein R₅ and R₂₀ togetheris a carbon-carbon bond; this structural feature imposes some desiredmolecular rigidity as an alternative to having bulky atoms at R₅, R₆ orR₇ or having R₅ and R₆ together forming a carbon-carbon bond or havingR₅, R₆ or R₇ as part of ring structures. Such a compound can beprepared, for example, by one skilled in the art using an approach suchas the following:

One skilled in the art can make such compounds through modification ofexisting compounds or precursors of formula Ia or IIa, and/or can useappropriate available commercially or routinely available precursors foruse as building blocks to synthesize the desired final compoundstructures, for example through use of one or more of the schemes I-XVI,or modifications or adaptations thereof or other approaches well-knownto those skilled in the art.

Example 2

¹H-NMR data are used to confirm the structures of exemplary compounds ofthe invention. Spectra are routinely recorded using DMSO-d⁶ or CDCl₃ assolvent, or other appropriate solvent when necessary. For illustrativepurposes, the NMR data of some selected exemplary compounds (ID numbersin bold) of the invention are provided as follows: compound 2096 (CDCl₃)8.547 (s, 1H); 8.515 (s, 1H); 7.706 (d, 1H, J=7.1 Hz); 7.509 (t, 1H,J=5.4 Hz); 7.194 (s, 1H); 6.830 (d, 1H, J=8.45 Hz); 6.789 (s, 2H); 6.629(t, 1H, J=9.1 Hz); 5.735 (br, 1H); 5.551 (br, 1H); 4.371 (d, 2H, J=4.5Hz); 3.901 (s, 6H); 3.587 (s, 2H); 2.211 (s, 3H); compound 2090: (CDCl₃)7.563 (dd, 1H, J₁=9.65 Hz, J₂=13.4 Hz); 7.413 (s, 1H); 7.231 (s, 1H);7.184 (d, 1H, J=2.0 Hz); 7.007 (d, 1H, J=8.85 Hz); 6.806 (s, 2H); 6.643(t, 1H, J=8.00 Hz); 6.520 (s, 1H); 6.373 (br, 1H); 5.731 (br, 1H); 4.608(d, 2H, J=5.25 Hz); 3.907 (s, 6H); 2.304 (s, 3H); compound 2183:(DMSO-d6) 8.330 (t, 1H, J=5.7 Hz); 7.589 (dd, 1H, J₁=5.4 Hz, J₂=8.45Hz); 7.303 (s, 1H); 7.196 (dd, 1H, J₁=9.45 Hz, J₂=25 Hz); 6.855 (s, 2H);6.227 (td, 1H, 9.1 Hz); 4.395 (d, 2H, J=5.65 Hz); 3.787 (s, 1H); 3.781(s, 6H); 2.091 (s, 3H); compound 1736: (DMSO-d6) 8.680 (t, 1H, J=5.85Hz); 8.476 (d, 1H, J=1.65 Hz); 8.454 (dd, 1H, J₁=4.75 Hz, J₂=1.45 Hz);7.193 (s, 1H); 7.6420 (d, 1H, J=7.85 Hz); 7.336 (dd, 1H), 7.332 (s, 1H);7.206 (dd, 1H, J₁=5.4 Hz, J₂=8.40 Hz); 7.058 (dd, 1H, J₁=9.4 Hz, J₂=2.40Hz); 6.712 (td, 1H, J₁=9.45 Hz, J₂=2.45 Hz); 6.593 (d, 1H, J=1.8 Hz);6.539 (d, 1H, J=1.8 Hz); 4.309 (d, 2H, J=5.85 Hz); 3.777 (s, 3H); 3.727(s, 3H); 3.488 (s, 2H); 2.118 (s, 3H); compound 2200. (DMSO-d6) 8.676(t, 1H, J=5.8 Hz); 8.475 (d, 1H, J=1.9 Hz); 8.447 (dd, 1H, J₁=4.75 Hz,J₂=1.5 Hz); 8.392 (s, br, 1H); 7.639 (d, 1H, J=7.80 Hz); 7.324 (dd, 1H,J1=7.95 Hz, J2=4.75 Hz), 7.242 (s, 1H); 7.068 (dd, 1H, J₁=9.4 Hz, J₂=2.5Hz); 6.983 (dd, 1H, J₁=8.4 Hz, J₂=5.35 Hz); 6.699 (td, 1H, J₁=9.45 Hz,J₂=2.5 Hz); 6.593 (d, 1H, J=1.8 Hz); 6.546 (d, 1H, J=1.8 Hz); 4.306 (d,2H, J=5.90 Hz); 3.762 (s, 3H); 3.750 (s, 3H); 3.482 (s, 1H); 3.174 (s,1H); 2.136 (s, 3H); 1.20 (s, 12H).

Example 3

Human cancer cell lines are obtained from the American Type CultureCollection (ATCC). Cells are cultured using standard methods inRPMI-1640 growth medium supplemented with 5% fetal bovine serum (FBS).CellTiter-Glo ATP cell growth assay reagents are obtained from Promegaand used according to the manufacturer's protocol. Cells are plated at adensity of 5,000 cells per well in 96-well microplates or 1,250 cellsper well in 384-well plates, then allowed to attach for at least 4 h.Test compounds are dissolved in dimethyl sulfoxide (DMSO), and thisworking stock is further diluted in growth medium for addition to cellcultures. Serial dilutions of the test compound are prepared in growthmedium containing an equal amount of DMSO not exceeding 0.2% finalconcentration. Each compound concentration is tested in at least 3separate samples per cell line. At the end of a 3-day treatment period,growth inhibition is analyzed using a bioluminescent assay of ATPconcentration (Promega CellTiter-Glo) according to the manufacturer'sprotocol. Resulting luminescence is measured using the luminescencecartridge of the Molecular Devices Spectramax Paradigm microplatereader. Relative growth inhibition for each sample is determined bycomparison with the values obtained for vehicle treated control samples.Growth inhibition values are plotted with the GraphPad Prism5 softwareusing the 4-parameter logistic fit to obtain IC₅₀ values, whichcorresponds to the growth inhibitory potency of the compound.

Example 4

For demonstration of the Ras inhibitory properties of the compounds foruse and usefulness according to the invention, any of the methods thatwe have disclosed and described extensively in WO 2016/100542 and WO2016/100546, particularly with the examples contained therein, may beemployed. This selected example illustrates the use of well-establishedhuman colon tumor cell lines with widely divergent Ras activation statusto determine tumor cell growth inhibitory activity (IC₅₀ values) and Rasselectivity values for some selected exemplary compounds of the presentinvention. Cell lines thus employed in this example are HCT-116, ahighly Ras-driven line expressing mutant Ras, and HT-29, anon-Ras-driven line expressing wild-type, non-mutated Ras. Cells areplated at 5000 cells/well in 96-well plates, ten-fold serial dilutionsof compounds are tested, each tested concentration in at least 3separate samples per cell line, and viable cell numbers are measuredusing the Cell Titer Glo ATP luminescence assay (Promega). Toillustrate, in a typical, representative experiment the following datawere obtained (compound ID numbers in bold; for each compound the firstvalue is micromolar IC₅₀ for HCT-116, the second value is micromolarIC₅₀ for HT-29, and the third value is the HT-29/HCT-116 “Ras InhibitorySelectivity Index” where numbers greater than one indicate Rasselectivity): compound 2096, 0.033, 9.00, 273; compound 2090, 0.300,13.0, 43; compound 2183, 0.420, 9.28, 22; compound 1736, 5.05, 5.59,1.11; compound 2200, 6.18, 6.65, 1.08; compound 1796, 0.212, 8.03, 38.FIGS. 5-7 provide examples of full data sets from which numericalvalues, including Ras selectivity indices, can be calculated; data setsare shown for selected exemplary compounds 2090, 2096 and 2183. FIGS.5-7 provide examples of full data sets from which numerical values,including Ras selectivity indices, can be calculated; data sets areshown for selected exemplary compounds 2090, 2096 and 2183.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any examples, or exemplary language (e.g., “such as”) providedherein, is intended merely to better illuminate the invention and doesnot pose a limitation on the scope of the invention unless otherwiseclaimed. No language in the specification should be construed asindicating any non-claimed element as essential to the practice of theinvention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1-41. (canceled)
 42. A compound, (Z)- or (E)-isomer, epimer,diastereomer, rotamer, or pharmaceutically acceptable salt thereof,wherein the compound is of formula IIa,

wherein: R₁, R₂, R₃, and R₄ are independently selected from hydrogen,halo, alkyl, hydroxyl, haloalkyl, alkylmercapto, cyano, alkyloxy andhaloalkyloxy; R₂₁ is —(CH₂)_(n)NR₂₂C(O)X; each of R₅, R₆, R₇, R₈, andR₂₂ is independently selected from hydrogen, alkyl, halo and hydroxyl;or R₅ and R₆ together is a carbon-carbon bond; R₉ and R₂₀ together is acarbon-carbon bond; or R₆ and R₇ together with the atom to which theyare attached form a ring; or R₅ and R₆ together with the atoms to whichthey are attached, form a ring; n is 1 or 2; X is selected from aryl,arylalkyl, and heterocyclylalkyl, where the heterocyclyl of theheterocyclylalkyl of the X is selected from 7-membered, 6-membered and5-membered heterocyclic rings, and the aryl of the aryl and arylalkyl,and the heterocyclyl of the heterocyclylalkyl, is optionally substitutedwith one or more of halo, alkyl, haloalkyl, hydroxyl, alkyloxy, amino,alkylamino, dialkylamino, mercapto, alkylmercapto, carboxamido,aldehydo, cyano, oxo, alkylcarbonyloxy and sulfonamido; each of R₁₂,R₁₃, R₁₅ and R₁₆ is independently selected from the group consisting ofhydrogen, halo, alkyl, cycloalkyl, haloalkyl, alkyloxy, haloalkyloxy,hydroxyl, carboxyl, formyloxy, hydroxyalkyl, aldehydo, amino,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, mercapto,alkylmercapto, cyano, cyanoalkyl, nitro and azido; R₁₄ is hydroxyl, oris a cleavable alcohol prodrug moiety, or is a substituted orunsubstituted group selected from the group consisting ofalkylsulfinyloxy, alkylsulfonyloxy, carbamate, alkyloxy,alkylcarbonyloxy, alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxy,heterocyclylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphonooxy,phosphonoalkyloxy, phosphonooxyalkyloxy, aminosulfonyloxy,polyethyleneglycoxy, borono, boronoalkyl, boronoalkyloxy, arylalkyloxy,aminocarbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy, hydroxyalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy and alkyloxyaminocarbonyloxy;wherein the alkyl, and the alkyl of the alkylmercapto, alkyloxyhaloalkyloxy, heterocyclylalkyl, cycloalkyl, haloalkyl, hydroxyalkyl,alkylamino, aminoalkyl, alkylaminoalkyl, dialkylamino, cyanoalkyl,alkylsulfinyloxy, alkylsulfonyloxy, alkylcarbonyloxy,alkylcarbonyloxyalkyloxy, aminocarbonyloxyalkyloxy,arylalkylcarbonyloxy, heterocyclylalkylcarbonyloxy, phosphonoalkyloxy,phosphonooxyalkyloxy, boronoalkyl, boronoalkyloxy, arylalkyloxy,aminocarbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy, hydroxyalkyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy and alkyloxyaminocarbonyloxy,each comprises 1-6 carbon atoms; and, wherein the aryl, and the aryl ofthe arylalkyl, arylcarbonyloxy, arylalkylcarbonyloxy, aryloxycarbonyloxyand arylalkyloxy, each comprises an aromatic carbocyclic ring of 6-10carbon atoms.
 43. The compound, (Z)- or (E)-isomer, epimer,diastereomer, rotamer, or pharmaceutically acceptable salt of saidcompound of claim 42, wherein X is selected from phenyl, benzyl, andheterocyclylmethyl, where the heterocyclyl of the heterocyclylmethyl ofthe X is selected from the group consisting of piperidinyl, oxanyl,thianyl, pyridinyl, pyranyl, thiopyranyl, piperazinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, pyrimidinyl, pyrazinyl,pyridizinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, trioxanyl,trithianyl, triazinyl, tetrazinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiaphenyl, pyrrolyl, furanyl, thiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolanyl, imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl,oxadiazolyl, thiadiazolyl, dithiazolyl and tetrazolyl, wherein thephenyl and the phenyl ring of the benzyl, and the heterocyclyl of theheterocyclylmethyl, is optionally substituted with one or more of halo,alkyl, haloalkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino,mercapto, alkylmercapto, carboxamido, aldehydo, cyano, oxo,alkylcarbonyloxy and sulfonamide.
 44. The compound, (Z)- or (E)-isomer,epimer, diastereomer, rotamer, or pharmaceutically acceptable salt ofsaid compound of claim 43, where the heterocyclyl of theheterocyclylmethyl of the X is selected from the group consisting offuranyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, dioxolanyl, pyrazolyl, pyridinyl and imidazolyl, whereinthe phenyl and the phenyl ring of the benzyl, and the heterocyclyl ofthe heterocyclylmethyl are optionally substituted with one or more ofhalo, alkyl, haloalkyl, hydroxy, alkyloxy, amino, alkylamino,dialkylamino, mercapto, alkylmercapto, and carboxamido.
 45. Thecompound, (Z)- or (E)-isomer, epimer, diastereomer, rotamer, orpharmaceutically acceptable salt of said compound of claim 44, wherein Xis heterocyclylmethyl, where the heterocyclyl of the heterocyclylmethylof the X is selected from the group consisting of furanyl, pyrrolyl,pyridinyl, oxazolyl, thiazolyl, dioxolanyl, imidazolyl, pyrazolyl andthiophenyl, wherein the heterocyclyl of the heterocyclylmethyl isoptionally substituted with one or more of halo, alkyl, trifluoromethyl,hydroxy and methoxy.
 46. The compound, (Z)- or (E)-isomer, epimer,diastereomer, rotamer, or pharmaceutically acceptable salt of saidcompound of claim 45, wherein the heterocyclylmethyl is selected fromthe group consisting of furan-2-ylmethyl, furan-3-ylmethyl,oxazol-2-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl,thiazol-2-ylmethyl, thiazol-4-ylmethyl, thiazol-5-ylmethyl,imidazol-2-ylmethyl, imidazol-4-ylmethyl, imidazol-5-ylmethyl,pyrazol-3-ylmethyl, pyrazol-4-ylmethyl, pyrazol-5-ylmethyl,dioxolan-2-ylmethyl, and dioxolan-4-ylmethyl.
 47. The compound, (Z)- or(E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound of claim 46, wherein theheterocyclylmethyl is selected from the group consisting ofoxazol-2-ylmethyl, thiazol-2-ylmethyl, imidazol-2-ylmethyl,pyrazol-4-ylmethyl, and dioxolan-2-ylmethyl.
 48. The compound, (Z)- or(E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound of claim 47, wherein theheterocyclylmethyl is pyridin-3-ylmethyl.
 49. The compound, (Z)- or(E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound of claim 42, wherein each of R₁, R₂, R₃and R₄ is independently selected from the group consisting of hydrogen,halo, alkyloxy and alkyl; n is 1; each of R₁₂, R₁₃, R₁₅ and R₁₆ isindependently selected from hydrogen, halo, alkyl, alkyloxy andhaloalkyloxy; R₁₄ is selected from alkyloxy, hydroxyl, and a cleavablealcohol prodrug moiety.
 50. The compound, (Z)- or (E)-isomer, epimer,diastereomer, rotamer, or pharmaceutically acceptable salt of saidcompound of claim 49, wherein R₂ is selected from halo and alkyloxy; R₁,R₃ and R₄ are hydrogen; and two of R₁₂, R₁₃, R₁₅ and R₁₆ areindependently selected from hydrogen, alkyloxy and haloalkyloxy.
 51. Thecompound, (Z)- or (E)-isomer, epimer, diastereomer, rotamer, orpharmaceutically acceptable salt of said compound of claim 50, whereinR₂ is selected from fluoro and methoxy; and R₁₂ and R₁₆ are hydrogens,52. The compound, (Z)- or (E)-isomer, epimer, diastereomer, rotamer, orpharmaceutically acceptable salt of said compound of claim 51, whereineach of R₁₃ and R₁₅ is independently selected from methoxy andtrifluoromethoxy; and R₁₄ is selected from hydroxyl and methoxy.
 53. Thecompound, (Z)- or (E)-isomer, epimer, diastereomer, rotamer, orpharmaceutically acceptable salt of said compound of claim 52, whereineach of R₁₃ and R₁₅ is methoxy; R₇ is hydrogen; R₈ is alkyl; R₁₄ ishydroxyl; and X is heterocyclylmethyl, where the heterocyclylmethyl ofthe X is pyridin-3-ylmethyl.
 54. The compound, (Z)- or (E)-isomer,epimer, diastereomer, rotamer, or pharmaceutically acceptable salt ofsaid compound of claim 42, wherein R₅ and R₆ together is a carbon-carbonbond.
 55. The compound of claim 42, selected from the group consistingof:(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1-methyl-1H-pyrrole-2-carboxamide(2085);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrrole-2-carboxamide(2086);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrrole-3-carboxamide(2087);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1-methyl-1H-pyrrole-3-carboxamide(2088);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)furan-3-carboxamide(2089);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)furan-2-carboxamide(2090);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(furan-3-yl)acetamide(2092);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-imidazole-4-carboxamide(2093);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1H-imidazol-5-yl)acetamide(2094);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1H-pyrazol-5-yl)acetamide(2095);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-3-yl)acetamide(2096);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-2-yl)acetamide(2097);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyridin-4-yl)acetamide(2098);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)nicotinamide(2100);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-phenylacetamide(2101);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)benzamide(2102);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-5-yl)acetamide(2103);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-2-yl)acetamide(2104);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(oxazol-4-yl)acetamide(2105);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(thiazol-5-yl)acetamide(2106);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-4-carboxamide(2107);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-5-carboxamide(2108);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)oxazole-2-carboxamide(2109);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-5-yl)acetamide(2110);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-3-yl)acetamide(2111);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(isoxazol-4-yl)acetamide(2112);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)isoxazole-5-carboxamide(2113);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(pyrazin-2-yl)acetamide(2114);(Z)-(4-((3-((1H-imidazole-4-carboxamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2115);(Z)-4-((3-((1H-imidazole-2-carboxamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyldimethylcarbamate (2116);(Z)-(4-((3-((2-(1H-imidazol-2-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2117);(Z)-(4-((3-((2-(1H-pyrazol-5-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2119);(Z)-4-((5-fluoro-2-methyl-3-((oxazole-4-carboxamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylethylcarbamate (2120);(Z)-4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl4-methylpiperazine-1-carboxylate (2121);(Z)-4-((5-fluoro-2-methyl-3-((oxazole-2-carboxamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyldimethylcarbamate (2122);(Z)-(4-((5-fluoro-3-((2-(isoxazol-4-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2123);(Z)-(4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2124);(Z)-4-((5-fluoro-2-methyl-3-((2-phenylacetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl4-methylpiperazine-1-carboxylate (2125);(Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylmorpholine-4-carboxylate (2126);(Z)-4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl4-methylpiperazine-1-carboxylate (2127);(Z)-4-((3-((2-(1H-imidazol-5-yl)acetamido)methyl)-5-fluoro-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylmorpholine-4-carboxylate (2128);(Z)-4-((5-fluoro-2-methyl-3-((2-(thiazol-5-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylmorpholine-4-carboxylate (2129);(Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenylethylcarbamate (2130);(Z)-(4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2131);(Z)-(4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2132);(Z)-(4-((5-fluoro-2-methyl-3-((2-(1-methyl-1H-pyrrol-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2133);(Z)-(4-((5-fluoro-3-((furan-2-carboxamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl)boronicacid (2134);(Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2135);(Z)-4-((5-fluoro-2-methyl-3-((2-(oxazol-5-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2136);(Z)-4-((5-fluoro-2-methyl-3-((2-(oxazol-4-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2137);(Z)-4-((5-fluoro-2-methyl-3-((2-phenylacetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2138);(Z)-4-((5-fluoro-2-methyl-3-((2-(pyridin-3-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2139);(Z)-4-((5-fluoro-3-((2-(isoxazol-5-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2140);(Z)-4-((5-fluoro-3-((2-(furan-2-yl)acetamido)methyl)-2-methyl-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2141);(Z)-4-((5-fluoro-2-methyl-3-((2-(1-methyl-1H-pyrrol-2-yl)acetamido)methyl)-1H-inden-1-ylidene)methyl)-2,6-dimethoxyphenyl[1,4′-bipiperidine]-1′-carboxylate (2142);(Z)-2-(1,3-dioxolan-2-yl)-N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)acetamide(2174);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(2-methyl-1,3-dioxolan-4-yl)acetamide(2175);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(thiazol-2-yl)acetamide(2176);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-2-(1,3-oxathiolan-2-yl)acetamide(2179);(Z)—N-((5-fluoro-1-(4-hydroxy-3,5-dimethoxybenzylidene)-2-methyl-1H-inden-3-yl)methyl)-1H-pyrazole-4-carboxamide(2183); or (E)-isomer thereof, epimer, diastereomer or rotamer thereof,or pharmaceutically acceptable salt thereof.
 56. A pharmaceuticalcomposition comprising at least one compound, (Z)- or (E)-isomer,epimer, diastereomer, rotamer, or pharmaceutically acceptable salt ofsaid compound, of claim 42, and a pharmaceutically acceptable carrier,said composition optionally containing at least one therapeutic agentthat is not a compound of claim 42 or (E)-isomer thereof, epimer,diastereomer or rotamer thereof or pharmaceutically acceptable saltthereof.
 57. A pharmaceutical composition comprising at least onecompound, (Z)- or (E)-isomer, epimer, diastereomer, rotamer, orpharmaceutically acceptable salt of said compound, of claim 55, and apharmaceutically acceptable carrier, said composition optionallycontaining at least one therapeutic agent that is not a compound ofclaim 42 or (E)-isomer thereof, epimer, diastereomer or rotamer thereofor pharmaceutically acceptable salt thereof.
 58. A method of treating apatient whose cancer has been assayed and found to contain a hyperactiveRas protein or a mutant ras gene encoding for a hyperactive Ras protein,the method comprising administering to the patient an effective amountof the compound of claim 42, (Z)- or (E)-isomer, epimer, diastereomer,rotamer, or pharmaceutically acceptable salt of said compound.
 59. Amethod of treating a patient whose cancer has been assayed and found tocontain a hyperactive Ras protein or a mutant ras gene encoding for ahyperactive Ras protein, the method comprising administering to thepatient an effective amount of the compound of claim 55, (Z)- or(E)-isomer, epimer, diastereomer, rotamer, or pharmaceuticallyacceptable salt of said compound.
 60. The method according to claim 58,wherein the patient's cancer is pancreatic cancer, lung cancer,colorectal cancer, melanoma, ovarian cancer, renal cancer, prostatecancer, head and neck cancer, endocrine cancer, uterine cancer, breastcancer, sarcoma cancer, gastric cancer, hepatic cancer, esophagealcancer, central nervous system cancer, brain cancer, hepatic cancer,germline cancer, lymphoma, or leukemia.
 61. The method according toclaim 60, wherein the patient's cancer is pancreatic cancer, colorectalcancer, or lung cancer.